Pyrazole derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors

ABSTRACT

The present invention relates to novel compounds of Formula (I), wherein M, P, X 1 , X 2 , (A) m  and (B) n  are defined as in Formula (I); invention compounds are modulators of metabotropic glutamate receptors—subtype 4 (“mGluR4”) which are useful for the treatment or prevention of central nervous system disorders as well as other disorders modulated by mGluR4 receptors. The invention is also directed to pharmaceutical compositions and the use of such compounds in the manufacture of medicaments, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR4 is involved.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of Formula (I), whereinM, P, X¹, X², (A)_(m) and (B)_(n) are defined as in Formula (I);invention compounds are modulators of metabotropic glutamatereceptors—subtype 4 (“mGluR4”) which are useful for the treatment orprevention of central nervous system disorders as well as otherdisorders modulated by mGluR4 receptors. The invention is also directedto pharmaceutical compositions and the use of such compounds in themanufacture of medicaments, as well as to the use of such compounds forthe prevention and treatment of such diseases in which mGluR4 isinvolved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino-acid transmitter in the mammalian centralnervous system (CNS). Glutamate plays a major role in numerousphysiological functions, such as learning and memory but also sensoryperception, development of synaptic plasticity, motor control,respiration and regulation of cardiovascular function. Furthermore,glutamate is at the center of several different neurological andpsychiatric diseases, where there is an imbalance in glutamatergicneurotransmission.

Glutamate mediates synaptic neurotransmission through the activation ofionotropic glutamate receptor channels (iGluRs), namely the NMDA, AMPAand kainate receptors which are responsible for fast excitatorytransmission (Nakanishi et al., (1998) Brain Res. Rev., 26:230-235).

In addition, glutamate activates metabotropic glutamate receptors(mGluRs) which have a more modulatory role that contributes to thefine-tuning of synaptic efficacy.

The mGluRs are G protein-coupled receptors (GPCRs) withseven-transmembrane spanning domains and belong to GPCR family 3 alongwith the calcium-sensing, GABAb and pheromone receptors.

The mGluR family is composed of eight members. They are classified intothree groups (group I comprising mGluR1 and mGluR5; group II comprisingmGluR2 and mGluR3; group III comprising mGluR4, mGluR6, mGluR7 andmGluR8) according to sequence homology, pharmacological profile andnature of intracellular signalling cascades activated (Schoepp et al.,(1999) Neuropharmacology, 38:1431-1476).

Glutamate activates the mGluRs through binding to the largeextracellular amino-terminal domain of the receptor, herein called theorthosteric binding site. This activation induces a conformationalchange of the receptor which results in the activation of the G-proteinand intracellular signalling pathways.

In the central nervous system, mGluR4 receptors are expressed mostintensely in the cerebellar cortex, basal ganglia, sensory relay nucleiof the thalamus and hippocampus (Bradley et al., (1999) Journal ofComparative Neurology, 407:33-46; Corti et al., (2002) Neuroscience,110:403-420). The mGluR4 subtype is negatively coupled to adenylatecyclase via activation of the Gαi/o protein, is expressed primarily onpresynaptic terminals, functioning as an autoreceptor or heteroceptorand activation of mGluR4 leads to decreases in transmitter release frompresynaptic terminals (Corti et al., (2002) Neuroscience, 110:403-420;Millan et al., (2002) Journal of Biological Chemistry, 277:47796-47803;Valenti et al., (2003) Journal of Neuroscience, 23:7218-7226).

Orthosteric agonists of mGluR4 are not selective and activate the otherGroup III mGluRs (Schoepp et al., (1999) Neuropharmacology,38:1431-1476). The Group III orthosteric agonist L-AP4(L-2-amino-4-phosphonobutyrate) was able to reduce motor deficits inanimal models of Parkinson's disease (Valenti et al., (2003) J.Neurosci., 23:7218-7226) and decrease excitotoxicity (Bruno et al.,(2000) J. Neurosci., 20; 6413-6420) and these effects appear to bemediated through mGluR4 (Marino et al., (2005) Curr. Topics Med. Chem.,5:885-895). In addition to L-AP4, ACPT-1, another selective group IIImGluR agonist has been shown to caused a dose-and-structure dependantdecrease in haloperidol-induced catalepsy and attenuatedhaloperidol-increased Proenkephalin mRNA expression in the striatum(Konieczny et al., (2007) Neuroscience, 145:611-620). Furthermore, Lopezet al. (2007, J. Neuroscience, 27:6701-6711) have shown that bilateralinfusions of ACPT-I or L-AP4 into the globus pallidus fully reversed thesevere akinetic deficits produced by 6-hydroxydopamine lesions ofnigrostriatal dopamine neurons in a reaction-time task without affectingthe performance of controls. In addition, the reversal ofhaloperidol-induced catalepsy by intrapallidal ACPT-1 was prevented byconcomitant administration of a selective group III receptor antagonist(RS)-alpha-cyclopropyl-4-phosphonophenylglycine. The opposite effectsproduced by group III mGluR activation in the SNr strongly suggest arole of mGluR4 rather than others mGluR receptor sub-types innormalizing basal ganglia activity (Lopez et al. 2007).

These results suggest that, among mGluR subtypes, mGluR4 is believed tobe the most interesting novel drug target for the treatment ofParkinson's disease (for a review see Conn et al., (2005) Nature ReviewNeuroscience, 6:787-798).

Symptoms of Parkinson's disease appear to be due to an imbalance in thedirect and indirect output pathways of the basal ganglia and reductionof transmission at the inhibitory GABAergic striato-pallidal synapse inthe indirect pathway may result in alleviation of these symptoms (Marinoet al., (2002) Amino Acids, 23:185-191).

mGluR4 is more abundant in striato-pallidal synapses than instriato-nigral synapses, and its localization suggests function as apresynaptic heteroreceptor on GABAergic neurons (Bradley et al., (1999)Journal of Comparative Neurology, 407:33-46) suggesting that selectiveactivation or positive modulation of mGluR4 would decrease GABA releasein this synapse thereby decreasing output of the indirect pathway andreducing or eliminating the Parkinson's disease symptoms. Classicaltreatment of Parkinsonism typically involves the use of levodopacombined with carbidopa (SINEMET™) or benserazide (MADOPAR™). Dopamineagonists such as bromocriptine (PARLODEL™), lisuride and pergolide(CELANCE™) act directly on dopamine receptors and are also used for thetreatment of Parkinsonism. These molecules have the same side-effectprofile as levodopa.

A new avenue for developing selective compounds acting at mGluRs is toidentify molecules that act through allosteric mechanisms, modulatingthe receptor by binding to a site different from the highly conservedorthosteric binding site.

Positive allosteric modulators of mGluRs have emerged recently as novelpharmacological entities offering this attractive alternative. This typeof molecule has been discovered for mGluR1, mGluR2, mGluR4, mGluR5,mGluR7 and mGluR8 (Knoflach F. et al. (2001) Proc. Natl. Acad. Sci. USA,98:13402-13407; Johnson M. P. et al., (2002) Neuropharmacology,43:799-808; O'Brien J. A. et al., (2003) Mol. Pharmacol., 64:731-740;Johnson M. P. et al., (2003) J. Med. Chem., 46:3189-3192; Marino M. J.et al., (2003) Proc. Natl. Acad. Sci. USA, 100:13668-13673; Mitsukawa K.et al., (2005) Proc. Natl. Acad. Sci. USA, 102(51):18712-18717; WilsonJ. et al., (2005) Neuropharmacology, 49:278; for a review see Mutel V.,(2002) Expert Opin. Ther. Patents, 12:1-8; Kew J. N., (2004) Pharmacol.Ther., 104(3):233-244; Johnson M. P. et al., (2004) Biochem. Soc.Trans., 32:881-887; recently Ritzen A., Mathiesen, J. M. and Thomsen C.,(2005) Basic Clin. Pharmacol. Toxicol., 97:202-213).

In particular molecules have been described as mGluR4 positiveallosteric modulators (Maj et al., (2003) Neuropharmacology, 45:895-906;Mathiesen et al., (2003) British Journal of Pharmacology,138:1026-1030). It has been demonstrated that such molecules have beencharacterized in in vitro systems as well as in rat brain slices wherethey potentiated the effect of L-AP4 in inhibiting transmission at thestriatopallidal synapse. These compounds do not activate the receptor bythemselves (Marino et al., (2003) Proc. Nat. Acad. Sci. USA,100:13668-13673). Rather, they enable the receptor to produce a maximalresponse to a concentration of glutamate or the Group III orthostericagonist L-AP4 which by itself induces a minimal response.

PHCCC (N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide), apositive allosteric modulator of mGluR4 not active on other mGluRs (Majet al., (2003) Neuropharmacology, 45:895-906), has been shown to beefficacious in animal models of Parkinson's disease thus representing apotential novel therapeutic approach for Parkinson's disease as well asfor other motor disorders and disturbances (Marino et al., (2003) Proc.Nat. Acad. Sci. USA, 100:13668-13673), neurodegeneration in Parkinson'sdisease (Marino et al., (2005) Curr. Topics Med. Chem., 5:885-895;Valenti et al., (2005) J. Pharmacol. Exp. Ther., 313:1296-1304; Vernonet al., (2005) Eur. J. Neurosci., 22:1799-1806, Battaglia et al., (2006)J. Neurosci., 26:7222-7229), and neurodegeneration in Alzheimer'sdisease or due to ischemic or traumatic insult (Maj et al., (2003)Neuropharmacology, 45:895-906).

PHCCC also has been shown to be active in an animal model of anxiety(Stachowicz et al., (2004) Eur. J. Pharmacol., 498:153-156). Previously,ACPT-1 has been shown to produce a dose-dependent anti-conflict effectafter intrahippocampal administration and anti-depressant-like effectsin rats after intracerebroventricular administration (Tatarczynska etal., (2002) Pol. J. Pharmacol., 54(6):707-710). More recently, ACPT-1has also been shown to have anxiolytic-like effects in thestress-induced hyperthermia, in the elevated-plus maze in the mice andin the Vogel conflict test in the rats when injected intraperitoneally(Stachowicz et al., (2009) Neuropharmacology, 57(3): 227-234).

Activation of mGluR4 receptors which are expressed in α- and F-cells inthe islets of Langerhans inhibits glucagon secretion. Molecules whichactivate or potentiate the agonist activity of these receptors may be aneffective treatment for hyperglycemia, one of the symptoms of type 2diabetes (Uehara et al., (2004) Diabetes, 53:998-1006).

The β-chemokine RANTES is importantly involved in neuronal inflammationand has been implicated in the pathophysiology of multiple sclerosis.Activation of Group III mGluRs with L-AP4 reduced the synthesis andrelease of RANTES in wild-type cultured astrocytes, whereas the abilityof L-AP4 to inhibit RANTES was greatly decreased in astrocyte culturesfrom mGluR4 knockout mice (Besong et al., (2002) Journal ofNeuroscience, 22:5403-5411). These data suggest that positive allostericmodulators of mGluR4 may be an effective treatment for neuroinflammatorydisorders of the central nervous system, including multiple sclerosisand related disorders.

Two different variants of the mGluR4 receptor are expressed in tastetissues and may function as receptors for the umami taste sensation(Monastyrskaia et al., (1999) Br. J Pharmacol., 128:1027-1034; Toyono etal., (2002) Arch. Histol. Cytol., 65:91-96). Thus positive allostericmodulators of mGluR4 may be useful as taste agents, flavour agents,flavour enhancing agents or food additives.

There is anatomical evidence that the majority of vagal afferentsinnervating gastric muscle express group III mGluRs (mGluR4, mGluR6,mGluR7 and mGluR8) and actively transport receptors to their peripheralendings (Page et al., (2005) Gastroenterology, 128:402-10). Recently, itwas shown that the activation of peripheral group III mGluRs inhibitedvagal afferents mechanosensitivity in vitro which translates intoreduced triggering of transient lower oesophageal sphincter relaxationsand gastroesophageal reflux in vivo (Young et al., (2008)Neuropharmacol, 54:965-975). Labelling for mGluR4 and mGluR8 wasabundant in gastric vagal afferents in the nodose ganglion, at theirtermination sites in the nucleus tractus solitarius and in gastric vagalmotoneurons. These data suggest that positive allosteric modulators ofmGluR4 may be an effective treatment for gastro-esophageal refluxdisease (GERD) and lower esophageal disorders and gastro-intestinaldisorders.

International patent publication WO2005/007096 describes mGluR4 receptorpositive allosteric modulator useful, alone or in combination with aneuroleptic agent, for treating or preventing movement disorders.However, none of the specifically disclosed compounds are structurallyrelated to the compounds of the invention. Also, international patentpublication WO2003/104223 describes the preparation of pyrazoles as p38αkinase, TNF and/or cyclooxygenase-2 inhibitors, international patentpublication WO2007/076473 shows the efficacy of substitutedpyrimidinyloxy ureas as inhibitors of protein kinases and internationalpatent publication WO98/56789 prepares pyrimidinyl azole as herbicides.

More recently, new mGluR4 receptor positive allosteric modulators havebeen described: pyrazolo[3,4-d]pyrimidine derivatives (Niswender et al.,(2008) Bioorganic & Medicinal Chemistry Letters, 18(20):5626-5630),functionalized benzylidene hydrazinyl-3-methylquinazoline andbis-2,3-dihydroquinazolin-4(1H)-one (Williams et al., (2009) Bioorganic& Medicinal Chemistry Letters, 19:962-966) and heterobiarylamides(Engers et al, (2009) Journal of Medicinal Chemistry, 52 (14),4115-4118). Niswender et al., described(±)-cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexane carboxylic acid(2008) Molecular Pharmacology, 74(5):1345-1358), as a positiveallosteric modulator of mGluR4 also having agonist activity. Thismoderately active molecule has demonstrated evidence of efficacyfollowing icy injection in rat models of Parkinson's disease.International patent publications WO2009/010454 and WO2009/010455 (UKpatent application: GB2455111) have mentioned amido derivatives andnovel heteroaromatic derivatives, respectively, as positive allostericmodulators of metabotropic glutamate receptors. The subject of thelatter case has been examined in the following article East Stephen P.et al., (2010) Expert Opin. Ther. Patents, 20 (3) 441-445. Finally,Williams R. et al., described in (2010) ACS Chemical Neuroscience, 1(6):411-419, the “Re-exploration of the PHCCC scaffold”.

-   (i) International patent publication WO2008/058096 describes    1-azatricyclo[3.3.1.13,7]decane,    4-[[4-(1H-pyrazol-4-yl)-2-thiazolyl]oxy] as ligand of nicotinic    acetylcholine receptors.-   (ii) International patent publication WO2008/001076 describes    6,6-dimethyl-2-(6-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yloxy)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one    as PI3 kinase inhibitors.

The present inventors have discovered novel pyrazole compounds ofgeneral Formula (I) which, surprisingly, show potent activity andselectivity on mGluR4 receptor. The compounds of the inventiondemonstrate advantageous properties over compounds of the prior art.Improvements have been observed in one or more of the followingcharacteristics of the compounds of the invention: the potency on thetarget, the selectivity for the target, the bioavailability, the brainpenetration, and the activity in behavioural models.

The present invention relates to a method of treating or preventing acondition in a mammal, including a human, the treatment or prevention ofwhich is affected or facilitated by the neuromodulatory effect of mGluR4modulators. In the case of the treatment of movement disorders such asParkinson's disease, the compounds of the invention can be used alone orin combination with a dopaminergic agent.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to compounds having metabotropic glutamatereceptor 4 modulator activity. In its most general compound aspect, thepresent invention provides a compound according to Formula (I),

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof,wherein:X¹ and X² are each independently selected from the group of C, N, S andC═C representing a 5 or 6 membered heteroaryl ring which may further besubstituted by radicals (A)_(m), and when X¹ is N, X² can not be C═C andwhen X² is N, X¹ can not be C═C;m is an integer ranging from 0 to 2;(A)_(m) radicals are each independently selected from the group ofhydrogen, halogen, —CN, —OH, —NO₂, —CF₃, —SH, —NH₂ and an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl, —(C₂-C₆)alkenyl, —(C₃-C₇)cycloalkyl,—(C₃-C₈)cycloalkenyl, —(C₁-C₆)cyanoalkyl, aryl, —(C₁-C₆)alkylene-aryl,heteroaryl, —(C₁-C₆)alkylene-heteroaryl, heterocycle,—(C₀-C₆)alkylene-OR¹, —O—(C₂-C₆)alkylene-OR¹, —NR¹(C₂-C₆)alkylene-OR²,—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—NR¹—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—NR¹—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)halo alkylene-OR¹,—(C₁-C₆)haloalkylene-NR¹R², —(C₃-C₆)alkynylene-OR¹,—(C₃-C₆)alkynylene-NR¹R², —(C₃-C₆)alkenylene-OR¹, —(C₃-C₆)alkenylene-NR¹R², —(C₀-C₆)alkylene-S—R¹, —O—(C₂-C₆)alkylene-S—R¹,—NR¹—(C₂-C₆)alkylene-S—R², —(C₀-C₆)alkylene-S(═O)—R¹,—O—(C₁-C₆)alkylene-S(═O)—R¹, —NR¹—(C₁-C₆)alkylene-S(═O)—R²,—(C₀-C₆)alkylene-S(═O)₂—R¹, —O—(C₁-C₆)alkylene-S(═O)₂—R¹,—NR¹—(C₁-C₆)alkylene-S(═O)₂—R², —(C₀-C₆)alkylene-NR¹R²,—O—(C₂-C₆)alkylene-NR¹R², —NR¹—(C₂-C₆)alkylene-NR²R³,—(C₀-C₆)alkylene-S(═O)₂NR¹R², —O—(C₁-C₆)alkylene-S(═O)₂NR¹R²,—NR¹—(C₁-C₆)alkylene-S(═O)₂NR²R³, —(C₀-C₆)alkylene-NR¹—S(═O)₂R²,—O—(C₂-C₆)alkylene-NR¹—S(═O)₂R², —NR¹—(C₂-C₆)alkylene-NR²—S(═O)₂R³,—(C₀-C₆)alkylene-C(═O)—NR¹R², —O—(C₁-C₆)alkylene-C(═O)—NR¹R²,—NR¹—(C₁-C₆)alkylene-C(═O)—NR²R³, —(C₀-C₆)alkylene-NR¹C(═O)—R²,—O—(C₂-C₆)alkylene-NR¹C(═O)—R², —NR¹—(C₂-C₆)alkylene-NR²C(═O)—R³,—(C₀-C₆)alkylene-OC(═O)—R¹, —O—(C₂-C₆)alkylene-OC(═O)—R¹,—NR¹—(C₂-C₆)alkylene-OC(═O)—R², —(C₀-C₆)alkylene-C(═O)—OR¹,—O—(C₁-C₆)alkylene-C(═O)—OR¹, —NR¹—(C₁-C₆)alkylene-C(═O)—OR²,—(C₀-C₆)alkylene-C(═O)—R¹, —O—(C₁-C₆)alkylene-C(═O)—R¹ and—NR¹—(C₁-C₆)alkylene-C(═O)—R²;R¹, R² and R³ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl, —(C₁-C₆)alkylene-heteroaryl,aryl, heterocycle and —(C₁-C₆)alkylene-aryl;Any two radicals of R (R¹, R² or R³) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;n is an integer ranging from 1 to 2;(B)_(n) radicals are each independently selected from the group ofhydrogen, halogen, —CN, —OH, —NO₂, —CF₃, —SH, —NH₂ and an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl, —(C₂-C₆)alkenyl, —(C₃-C₇)cycloalkyl,—(C₃-C₈)cycloalkenyl, —(C₁-C₆)cyanoalkyl, —(C₁-C₆)alkylene-hetero aryl,—(C₁-C₆)alkylene-aryl, aryl, heteroaryl, heterocycle,—(C₀-C₆)alkylene-OR⁴, —O—(C₂-C₆)alkylene-OR⁴, —NR⁴(C₂-C₆)alkylene-OR⁵,—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—NR⁴—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—NR⁴—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)haloalkylene-OR⁴,—(C₁-C₆)haloalkylene-NR⁴R⁵, —(C₃-C₆)alkynylene-OR⁴,—(C₃-C₆)alkynylene-NR⁴R⁵, —(C₃-C₆)alkenylene-OR⁴,—(C₃-C₆)alkenylene-NR⁴R⁵, —(C₀-C₆)alkylene-S—R⁴,—O—(C₂-C₆)alkylene-S—R⁴, —NR⁴—(C₂-C₆)alkylene-S—R⁵,—(C₀-C₆)alkylene-S(═O)—R⁴, —O—(C₁-C₆)alkylene-S(═O)—R⁴,—NR⁴—(C₁-C₆)alkylene-S(═O)—R⁵, —(C₀-C₆)alkylene-S(═O)₂—R⁴,—O—(C₁-C₆)alkylene-S(═O)₂—R⁴, —NR⁴—(C₁-C₆)alkylene-S(═O)₂—R⁵,—(C₀-C₆)alkylene-NR⁴R⁵, —O—(C₂-C₆)alkylene-NR⁴R⁵,—NR⁴—(C₂-C₆)alkylene-NR⁵R⁶, —(C₀-C₆)alkylene-S(═O)₂NR⁴R⁵,—O—(C₁-C₆)alkylene-S(═O)₂NR⁴R⁵, —NR⁴—(C₁-C₆)alkylene-S(═O)₂NR⁵R⁶,—(C₀-C₆)alkylene-NR⁴—S(═O)₂R⁵, —O—(C₂-C₆)alkylene-NR⁴—S(═O)₂R⁵,—NR⁴—(C₂-C₆)alkylene-NR⁵—S(═O)₂R⁶, —(C₀-C₆)alkylene-C(═O)—NR⁴R⁵,—O—(C₁-C₆)alkylene-C(═O)—NR⁴R⁵, —NR⁴—(C₁-C₆)alkylene-C(═O)—NR⁵R⁶,—(C₀-C₆)alkylene-NR⁴C(═O)—R⁵, —O—(C₂-C₆)alkylene-NR⁴C(═O)—R⁵,—NR⁴—(C₂-C₆)alkylene-NR⁵C(═O)—R⁶, —(C₀-C₆)alkylene-OC(═O)—R⁴,—O—(C₂-C₆)alkylene-OC(═O)—R⁴, —NR⁴—(C₂-C₆)alkylene-OC(═O)—R⁵,—(C₀-C₆)alkylene-C(═O)—OR⁴, —O—(C₁-C₆)alkylene-C(═O)—OR⁴,—NR⁴—(C₁-C₆)alkylene-C(═O)—OR⁵, —(C₀-C₆)alkylene-C(═O)—R⁴,—O—(C₁-C₆)alkylene-C(═O)—R⁴ and —NR⁴—(C₁-C₆)alkylene-C(═O)—R⁵;R⁴, R⁵ and R⁶ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₄-C₀)alkylene-cycloalkyl, heteroaryl, —(C₁-C₆)alkylene-heteroaryl,aryl, heterocycle and —(C₁-C₆)alkylene-aryl;Any two radicals of R(R⁴, R⁵ or R⁶) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;M is selected from an optionally substituted 3 to 10 membered ringselected from the group of aryl, heteroaryl, heterocyclic andcycloalkyl;P is selected from the group of a hydrogen or an optionally substitutedradical selected from the group of —(C₀-C₆)alkylene-R⁷,—(C₀-C₆)haloalkyl, —(C₂-C₆)alkylene-NR⁷R⁸, —(C₂-C₆)alkylene-OR⁷,—(C₂-C₆)alkylene-SR⁷, —(C₀-C₆)alkylene-C(═O)—R⁷,—(C₂-C₆)alkylene-S(O)—R⁷, —(C₀-C₆)alkylene-C(═O)NR⁷R⁸,—(C₀-C₆)alkylene-NR⁷C(═O)R⁸ and —(C₀-C₆)alkylene-S(O)₂—R⁷;R⁷ and R⁸ are selected from the group of a hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl, —(C₁-C₆)alkylene-heteroaryl,aryl, heterocycle and —(C₁-C₆)alkylene-aryl;with the proviso (i) that:M can not be an azaadamantanyl;with the proviso (ii) that: andM can not be 3,4-Dihydro-2H-Benzo[b][1,4]oxazine.

In a more preferred aspect of Formula (I), the invention provides acompound according to Formula (II):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof,wherein:X² is selected from the group of C and N representing a 5 memberedheteroaryl ring which may further be substituted by radical (A)_(m)where:m is an integer ranging from 0 to 1;(A)_(m) radical is selected from the group of hydrogen, halogen, —CN,—OH, —CF₃, —SH, —NH₂ and an optionally substituted radical selected fromthe group of —(C₁-C₆)alkyl, —(C₁-C₆)halo alkyl, —(C₂-C₆)alkynyl,—(C₂-C₆)alkenyl, —(C₃-C₇)cycloalkyl, —(C₃-C₈)cycloalkenyl, —(C₁-C₆)cyanoalkyl, aryl, —(C₁-C₆)alkylene-aryl, heteroaryl, —(C₁-C₆)alkylene-heteroaryl, heterocycle, —(C₀-C₆)alkylene-OR¹, —O—(C₂-C₆)alkylene-OR¹,—NR¹(C₂-C₆)alkylene-OR², —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR¹—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—NR¹—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)haloalkylene-OR¹,—(C₁-C₆)halo alkylene-NR¹R², —(C₀-C₆)alkylene-S—R¹,—O—(C₂-C₆)alkylene-S—R¹, —NR¹—(C₂-C₆)alkylene-S—R²,—(C₀-C₆)alkylene-S(═O)—R¹, —O—(C₁-C₆)alkylene-S(═O)—R¹,—NR¹—(C₁-C₆)alkylene-S(═O)—R², —(C₀-C₆)alkylene-S(═O)₂—R¹,—O—(C₁-C₆)alkylene-S(═O)₂—R¹, —NR¹—(C₁-C₆)alkylene-S(═O)₂—R²,—(C₀-C₆)alkylene-NR¹R², —O—(C₂-C₆)alkylene-NR¹R²,—NR¹—(C₂-C₆)alkylene-NR²R³, —(C₀-C₆)alkylene-S(═O)₂NR¹R²,—O—(C₁-C₆)alkylene-S(═O)₂NR¹R², —NR¹—(C₁-C₆)alkylene-S(═O)₂NR²R³,—(C₀-C₆)alkylene-NR¹—S(═O)₂R², —O—(C₂-C₆)alkylene-NR¹—S(═O)₂R²,—NR¹—(C₂-C₆)alkylene-NR²—S(═O)₂R³, —(C₀-C₆)alkylene-C(═O)—NR¹R²,—O—(C₁-C₆)alkylene-C(═O)—NR¹R², —NR¹—(C₁-C₆)alkylene-C(═O)—NR²R³,—(C₀-C₆)alkylene-NR C(═O)—R², —O—(C₂-C₆)alkylene-NR¹C(═O)—R²,—NR¹—(C₂-C₆)alkylene-NR²C(═O)—R³, —(C₀-C₆)alkylene-C(═O)—R¹,—O—(C₁-C₆)alkylene-C(═O)—R¹ and —NR¹—(C₁-C₆)alkylene-C(═O)—R²;R¹, R² and R³ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl, —(C₁-C₆)alkylene-heteroaryl,aryl, heterocycle and —(C₁-C₆)alkylene-aryl;Any two radicals of R (R¹, R² or R³) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;B radical is selected from the group of hydrogen, halogen, —CN, —OH,—CF₃, —SH, —NH₂ and an optionally substituted radical selected from thegroup of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl,—(C₂-C₆)alkenyl, —(C₃-C₇)cycloalkyl, —(C₃-C₈)cycloalkenyl, —(C₁-C₆)cyanoalkyl, —(C₁-C₆)alkylene-hetero aryl, —(C₁-C₆)alkylene-aryl, aryl,heteroaryl, heterocycle, —(C₀-C₆)alkylene-OR⁴, —O—(C₂-C₆)alkylene-OR⁴,—NR⁴(C₂-C₆)alkylene-OR⁵, —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR⁴—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—NR⁴—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)haloalkylene-OR⁴,—(C₁-C₆)haloalkylene-NR⁴R⁵, —(C₀-C₆)alkylene-S—R⁴,—O—(C₂-C₆)alkylene-S—R⁴, —NR⁴—(C₂-C₆)alkylene-S—R⁵,—(C₀-C₆)alkylene-S(═O)—R⁴, —O—(C₁-C₆)alkylene-S(═O)—R⁴,—NR⁴—(C₁-C₆)alkylene-S—(C₀-C₆)alkylene-S(═O)₂—R⁴,—O—(C₁-C₆)alkylene-S(═O)₂—R⁴, —NR⁴—(C₁-C₆)alkylene-S(═O)₂—R⁵,—(C₀-C₆)alkylene-NR⁴R⁵, —O—(C₂-C₆)alkylene-NR⁴R⁵,—NR⁴—(C₂-C₆)alkylene-NR⁵R⁶, —(C₀-C₆)alkylene-S(═O)₂NR⁴R⁵,—O—(C₁-C₆)alkylene-S(═O)₂NR⁴R⁵, —NR⁴—(C₁-C₆)alkylene-S(═O)₂NR⁵R⁶,—(C₀-C₆)alkylene-NR⁴—S(═O)₂R⁵, —O—(C₂-C₆)alkylene-NR⁴—S(═O)₂R⁵,—NR⁴—(C₂-C₆)alkylene-NR⁵—S(═O)₂R⁶, —(C₀-C₆)alkylene-C(═O)—NR⁴R⁵,—O—(C₁-C₆)alkylene-C(═O)—NR⁴R⁵, —NR⁴—(C₁-C₆)alkylene-C(═O)—NR⁵R⁶,—(C₀-C₆)alkylene-NR⁴C(═O)—R⁵, —O—(C₂-C₆)alkylene-NR⁴C(═O)—R⁵,—NR⁴—(C₂-C₆)alkylene-NR⁵C(═O)—R⁶, —(C₀-C₆)alkylene-C(═O)—R⁴,—O—(C₁-C₆)alkylene-C(═O)—R⁴ and —NR⁴—(C₁-C₆)alkylene-C(═O)—R⁵;R⁴, R⁵ and R⁶ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl, —(C₁-C₆)alkylene-hetero aryl,aryl, heterocycle and —(C₁-C₆)alkylene-aryl;Any two radicals of R (R⁴, R⁵ or R⁶) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring; andwith the proviso (i) that:M can not be an azaadamantanyl.

In a more preferred aspect of Formula (II), the invention provides acompound according to Formula (III):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof,wherein:M is selected from an optionally substituted 3 to 10 membered ringselected from the group of aryl, heteroaryl and cycloalkyl.

In a more preferred aspect of Formula (III), the invention provides acompound wherein:

A radical is selected from the group of hydrogen, halogen, —CN, —CF₃,and an optionally substituted radical selected from the group of—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl, aryl, heteroaryl,heterocycle, —(C₀-C₆)alkylene-OR¹, —NR¹(C₂-C₆)alkylene-OR²,—(C₀-C₆)alkylene-NR¹R², —NR¹—(C₂-C₆)alkylene-NR²R³,—(C₀-C₆)alkylene-C(═O)—NR¹R² and —(C₀-C₆)alkylene-C(═O)—R¹;R¹ and R² are each independently hydrogen or an optionally substitutedradical selected from the group of —(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl,—(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl, —(C₄-C₁₀)alkylene-cycloalkyl,heteroaryl, —(C₁-C₆)alkylene-hetero aryl, aryl,—(C₁-C₆)alkylene-heterocycle, heterocycle and —(C₁-C₆)alkylene-aryl;Any two radicals of R (R¹ or R²) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;B radical is selected from the group of hydrogen, halogen, —CN, —CF₃ andan optionally substituted radical selected from the group of—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl, aryl, heteroaryl,heterocycle, —(C₀-C₆)alkylene-OR⁴, —NR¹(C₂-C₆)alkylene-OR²,—(C₀-C₆)alkylene-NR⁴R⁵, —O—(C₂-C₆)alkylene-NR⁴R⁵,—NR⁴—(C₂-C₆)alkylene-NR⁵R⁶, —(C₀-C₆)alkylene-C(═O)—NR⁴R⁵ and—(C₀-C₆)alkylene-C(═O)—R⁴;R⁴ and R⁵ are each independently hydrogen or an optionally substitutedradical selected from the group of —(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl,—(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl, —(C₄-C₁₀)alkylene-cycloalkyl,heteroaryl, —(C₁-C₆)alkylene-hetero aryl, aryl, heterocycle and—(C₁-C₆)alkylene-aryl; andAny two radicals of R (R⁴ or R⁵) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring.

In a more preferred aspect of Formula (III), the invention provides acompound wherein:

A radical is selected from the group of hydrogen, halogen and —CN;

B radical is selected from the group of hydrogen, halogen, —CF₃ and anoptionally substituted radical selected from the group of —(C₁-C₆)alkyl,and —(C₀-C₆)alkylene-C(═O)—R⁴; and

R⁴ is —(C₁-C₆)alkyl.

In a more preferred aspect of Formula (I), the invention provides acompound according to Formula (IV):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof.

In a more preferred aspect of Formula (IV), the invention provides acompound wherein:

B radical is selected from the group of hydrogen, —CF₃ and an optionallysubstituted radical —(C₁-C₆)alkyl; and

M is selected from an optionally substituted 3 to 10 membered ringselected from the group of aryl and heteroaryl.

In a more preferred aspect of Formula (I), the invention provides acompound according to Formula (V):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof,wherein:X¹ is selected from the group of C and N, which may further besubstituted by radicals (A)_(m) where:m is an integer ranging from 0 to 1;(A)_(m) radical is selected from the group of hydrogen, halogen, —CN,—CF₃, and an optionally substituted radical selected from the group of—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)cyanoalkyl, aryl, —(C₁-C₆)alkylene-aryl, heteroaryl,—(C₁-C₆)alkylene-heteroaryl, heterocycle, —(C₀-C₆)alkylene-OR¹,—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—(C₁-C₆)halo alkyl-OR¹, —(C₁-C₆)halo alkyl-NR¹R²,—(C₁-C₆)alkylene-C(═O)—NR²R³, —(C₀-C₆)alkylene-NR¹C(═O)—R²,—(C₀-C₆)alkylene-OC(═O)—R¹, —(C₀-C₆)alkylene-C(═O)—OR¹ and—(C₀-C₆)alkylene-C(═O)—R¹;R¹, R² and R³ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl, —(C₁-C₆)alkylene-hetero aryl,aryl, heterocycle and —(C₁-C₆)alkylene-aryl;Any two radicals of R (R¹, R² or R³) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;B radical is selected from the group of hydrogen, halogen, —CN, —CF₃,and an optionally substituted radical selected from the group of—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)cyanoalkyl, —(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-aryl, aryl,heteroaryl, heterocycle, —(C₀-C₆)alkylene-OR⁴, —O—(C₂-C₆)alkylene-OR⁴,—NR⁴(C₂-C₆)alkylene-OR⁵, —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR⁴—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—NR⁴—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)haloalkylene-OR⁴,—(C₁-C₆)haloalkylene-NR⁴R⁵, —(C₀-C₆)alkylene-NR⁴R⁵,—O—(C₂-C₆)alkylene-NR⁴R⁵, —NR⁴—(C₂-C₆)alkylene-NR⁵R⁶,—(C₀-C₆)alkylene-OC(═O)—R⁴, —O—(C₂-C₆)alkylene-OC(═O)—R⁴,—NR⁴—(C₂-C₆)alkylene-OC(═O)—R⁵, —(C₀-C₆)alkylene-C(═O)—OR⁴,—O—(C₁-C₆)alkylene-C(═O)—OR⁴, —NR⁴—(C₁-C₆)alkylene-C(═O)—OR⁵,—(C₀-C₆)alkylene-C(═O)—NR⁴R⁵, —(C₀-C₆)alkylene-C(═O)—R⁴,—O—(C₁-C₆)alkylene-C(═O)—R⁴ and —NR⁴—(C₁-C₆)alkylene-C(═O)—R⁵;R⁴, R⁵ and R⁶ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylene-cycloalkyl, hetero aryl, —(C₁-C₆)alkylene-hetero aryl,aryl, heterocycle and —(C₁-C₆)alkylene-aryl; andAny two radicals of R(R⁴, R⁵ or R⁶) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring.

Particular preferred compounds of the invention are compounds asmentioned in the following list (List of Particular PreferredCompounds), as well as a pharmaceutically acceptable acid or baseaddition salt thereof, a stereochemically isomeric form thereof and anN-oxide form thereof:

-   3-(3-Methyl-1H-pyrazol-4-yl)-5-phenoxy-1,2,4-thiadiazole-   5-(Pyridin-2-yloxy)-3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazole-   5-(6-Chloropyridin-2-yloxy)-3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazole-   4-(5-Methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yloxy)thiazole-   2-(2,6-Difluorophenoxy)-4-(1H-pyrazol-4-yl)thiazole-   4-(1H-Pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-   2-(6-Chloropyridin-2-yloxy)-4-(3-methyl-1H-pyrazol-4-yl)thiazole-   2-(3-Fluoropyridin-2-yloxy)-4-(3-methyl-1H-pyrazol-4-yl)thiazole-   1-(4-(2-(6-Methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazol-3-yl)ethanone-   2-(6-Methylpyridin-2-yloxy)-4-(1H-pyrazol-4-yl)thiazole-   4-(3-Methyl-1H-pyrazol-4-yl)-2-(6-methylpyridin-2-yloxy)thiazole-   2-(6-Chloropyridin-2-yloxy)-4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-   2-(Pyridin-2-yloxy)-4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-   2-(Cyclohexyloxy)-4-(1H-pyrazol-4-yl)thiazole-   2-(2,4-Difluorophenoxy)-4-(1H-pyrazol-4-yl)thiazole-   2-(6-Methylpyrazin-2-yloxy)-4-(1H-pyrazol-4-yl)thiazole-   1-(4-(2-(2,4-Difluorophenoxy)thiazol-4-yl)-1H-pyrazol-3-yl)ethanone-   2-(5-Fluoropyridin-2-yloxy)-4-(1H-pyrazol-4-yl)thiazole-   5-Chloro-4-(1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-   4-(1H-Pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile and-   2-(6-Chloropyridin-2-yloxy)-4-(1H-pyrazol-4-yl)thiazole-5-carbonitrile.

The disclosed compounds also include all pharmaceutically acceptableisotopic variations, in which at least one atom is replaced by an atomhaving the same atomic number, but an atomic mass different from theatomic mass usually found in nature. Examples of isotopes suitable forinclusion in the disclosed compounds include, without limitation,isotopes of hydrogen, such as ²H and ³H; isotopes of carbon, such as ¹³Cand ¹⁴C; isotopes of nitrogen, such as ¹⁵N; isotopes of oxygen, such as¹⁷O and ¹⁸O; isotopes of phosphorus, such as ³²P and ³³P; isotopes ofsulfur, such as ³⁵S; isotopes of fluorine, such as ¹⁸F; and isotopes ofchlorine, such as ³⁶Cl. Use of isotopic variations (e.g., deuterium, ²H)may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements. Additionally, certain isotopic variations of thedisclosed compounds may incorporate a radioactive isotope (e.g.,tritium, ³H, or ¹⁴C), which may be useful in drug and/or substratetissue distribution studies. Substitution with positron emittingisotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in PositronEmission Topography (PET) studies for examining substrate receptoroccupancy. Isotopically-labelled compounds of Formula (I) can generallybe prepared by conventional techniques known to those skilled in the artor by processes analogous to those described in the accompanyingExamples using appropriate isotopically-labeled reagents in place of thenon-labeled reagent previously employed.

Definition of Terms

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

For the avoidance of doubt it is to be understood that in thisspecification “(C₁-C₆)” means a carbon radical having 1, 2, 3, 4, 5 or 6carbon atoms. “(C₀-C₆)” means a carbon radical having 0, 1, 2, 3, 4, 5or 6 carbon atoms. In this specification “C” means a carbon atom, “N”means a nitrogen atom, “N” means an oxygen atom and “S” means a sulphuratom.

In the case where a subscript is the integer 0 (zero) the radical towhich the subscript refers, indicates that the radical is absent, i.e.there is a direct bond between the radicals.

In the case where a subscript is the integer 0 (zero) and the radical towhich the subscript refers is alkyl, this indicates the radical is ahydrogen atom.

In this specification, unless stated otherwise, the term “bond” refersto a saturated covalent bond. When two or more bonds are adjacent to oneanother, they are assumed to be equal to one bond. For example, aradical -A-B—, wherein both A and B may be a bond, the radical isdepicting a single bond.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl radicals and may bemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl or t-hexyl.The term “(C₀-C₃)alkyl” refers to an alkyl radical having 0, 1, 2 or 3carbon atoms and may be methyl, ethyl, n-propyl and i-propyl.

In this specification, unless stated otherwise, the term “alkylene”includes both straight and branched difunctional saturated hydrocarbonradicals and may be methylene, ethylene, n-propylene, i-propylene,n-butylene, i-butylene, s-butylene, t-butylene, n-pentylene,i-pentylene, t-pentylene, neo-pentylene, n-hexylene, i-hexylene ort-hexylene.

In this specification, unless stated otherwise, the term “cycloalkyl”refers to an optionally substituted carbocycle containing noheteroatoms, including mono-, bi-, and tricyclic saturated carbocycles,as well as fused ring systems. Such fused ring systems can include onering that is partially or fully unsaturated such as a benzene ring toform fused ring systems such as benzo-fused carbocycles. Cycloalkylincludes such fused ring systems as spirofused ring systems. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,decahydronaphthalene, adamantane, indanyl, fluorenyl and1,2,3,4-tetrahydronaphthalene and the like. The term “(C₃-C₇)cycloalkyl”may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andthe like.

The term “aryl” refers to an optionally substituted monocyclic orbicyclic hydrocarbon ring system containing at least one unsaturatedaromatic ring. Examples and suitable values of the term “aryl” arephenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl, indenyl and thelike.

In this specification, unless stated otherwise, the term “heteroaryl”refers to an optionally substituted monocyclic or bicyclic unsaturated,aromatic ring system containing at least one heteroatom selectedindependently from N, O or S. Examples of “heteroaryl” may be, but arenot limited to thienyl, pyridinyl, thiazolyl, isothiazolyl, furyl,pyrrolyl, triazolyl, imidazolyl, triazinyl, oxadiazolyl, oxazolyl,isoxazolyl, pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl,tetrazolyl, thiadiazolyl, benzoimidazolyl, benzooxazolyl,benzothiazolyl, tetrahydrotriazolopyridinyl,tetrahydrotriazolopyrimidinyl, benzofuryl, benzothiophenyl,thionaphthyl, indolyl, isoindolyl, pyridonyl, pyridazinyl, pyrazinyl,pyrimidinyl, quinolyl, phtalazinyl, naphthyridinyl, quinoxalinyl,quinazolyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl,imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, cynnolyl,pteridinyl, furazanyl, benzotriazolyl, pyrazolopyridinyl and purinyl.

In this specification, unless stated otherwise, the term“alkylene-aryl”, “alkylene-heteroaryl” and “alkylene-cycloalkyl” refersrespectively to a substituent that is attached via the alkyl radical toan aryl, heteroaryl or cycloalkyl radical, respectively. The term“(C₁-C₆)alkylene-aryl” includes aryl-C₁-C₆-alkyl radicals such asbenzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl,3-phenylpropyl, 1-naphthylmethyl and 2-naphthylmethyl. The term“(C₁-C₆)alkylene-heteroaryl” includes heteroaryl-C₁-C₆-alkyl radicals,wherein examples of heteroaryl are the same as those illustrated in theabove definition, such as 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl,3-thienylmethyl, 1-imidazolylmethyl, 2-imidazolylmethyl,3-imidazolylmethyl, 2-oxazolylmethyl, 3-oxazolylmethyl,2-thiazolylmethyl, 3-thiazolylmethyl, 2-pyridinylmethyl,3-pyridinylmethyl, 4-pyridinylmethyl, 1-quinolylmethyl or the like.

In this specification, unless stated otherwise, the term “heterocycle”refers to an optionally substituted, monocyclic or bicyclic saturated,partially saturated or unsaturated ring system containing at least oneheteroatom selected independently from N, O and S.

In this specification, unless stated otherwise, a 5- or 6-membered ringcontaining one or more atoms independently selected from C, N, O and S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Examples ofsuch rings may be, but are not limited to, furyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl,imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl,piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinonyl,thiomorpholinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl,cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl.

In this specification, unless stated otherwise, a 3- to 10-membered ringcontaining one or more atoms independently selected from C, N, O and S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Examples ofsuch rings may be, but are not limited to imidazolidinyl, imidazolinyl,morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl,pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, dihydropyrrolylisoxazolyl, isothiazolyl, isoindolinonyl,dihydropyrrolo[1,2-b]pyrazolyl, oxazolyl, oxazolidinonyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl,pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, phenyl,cyclopropyl, aziridinyl, cyclobutyl, azetidinyl, oxadiazolyl,thiadiazolyl, tetrazolyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and cyclooctenyl.

In this specification, unless stated otherwise, the term “halo” or“halogen” may be fluoro, chloro, bromo or iodo.

In this specification, unless stated otherwise, the term “haloalkyl”means an alkyl radical as defined above, substituted with one or morehalo radicals. The term “(C₁-C₆)haloalkyl” may include, but is notlimited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyland difluoroethyl. The term “O—C₁-C₆-haloalkyl” may include, but is notlimited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy andfluoroethoxy.

In this specification, unless stated otherwise, the term “haloalkylene”means an alkylene radical as defined above, substituted with one or morehalo radicals. The term “(C₁-C₆)haloalkylene” may include, but is notlimited to, fluoromethylene, difluoromethylene, fluoroethylene anddifluoroethylene. The term “O—C₁-C₆-haloalkylene” may include, but isnot limited to, fluoromethylenoxy, difluoromethylenoxy andfluoroethylenoxy.

In this specification, unless stated otherwise, the term “cyanoalkyl”means an alkyl radical as defined above, substituted with one or morecyano.

In this specification, unless stated otherwise, the term “optionallysubstituted” refers to radicals further bearing one or more substituentswhich may be, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkylene-oxy, mercapto,aryl, heterocycle, heteroaryl, (C₁-C₆)alkylene-aryl,(C₁-C₆)alkylene-heterocycle, (C₁-C₆)alkylene-heteroaryl, halogen,trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino,amido, amidinyl, carboxyl, carboxamide, (C₁-C₆)alkylene-oxycarbonyl,carbamate, sulfonamide, ester and sulfonyl.

In this specification, unless stated otherwise, the term “solvate”refers to a complex of variable stoichiometry formed by a solute (e.g. acompound of Formula (I)) and a solvent. The solvent is apharmaceutically acceptable solvent as preferably water; such solventmay not interfere with the biological activity of the solute.

In this specification, unless stated otherwise, the term “positiveallosteric modulator of mGluR4” or “allosteric modulator of mGluR4”refers also to a pharmaceutically acceptable acid or base addition saltthereof, a stereochemically isomeric form thereof and an N-oxide formthereof.

Pharmaceutical Compositions

Allosteric modulators of mGluR4 described herein, and thepharmaceutically acceptable salts, solvates and hydrates thereof can beused in pharmaceutical preparations in combination with apharmaceutically acceptable carrier or diluent. Suitablepharmaceutically acceptable carriers include inert solid fillers ordiluents and sterile aqueous or organic solutions. The allostericmodulators of mGluR4 will be present in such pharmaceutical compositionsin amounts sufficient to provide the desired dosage amount in the rangedescribed herein. Techniques for formulation and administration of thecompounds of the instant invention can be found in Remington: theScience and Practice of Pharmacy, 19^(th) edition, Mack Publishing Co.,Easton, Pa. (1995).

The amount of allosteric modulators of mGluR4, administered to thesubject will depend on the type and severity of the disease or conditionand on the characteristics of the subject, such as general health, age,sex, body weight and tolerance to drugs. The skilled artisan will beable to determine appropriate dosages depending on these and otherfactors. Effective dosages for commonly used CNS drugs are well known tothe skilled person. The total daily dose usually ranges from about0.05-2000 mg.

The present invention relates to pharmaceutical compositions whichprovide from about 0.01 to 1000 mg of the active ingredient per unitdose. The compositions may be administered by any suitable route. Forexample orally in the form of capsules and the like, parenterally in theform of solutions for injection, topically in the form of onguents orlotions, ocularly in the form of eye-drops, rectally in the form ofsuppositories, intranasally or transcutaneously in the form of deliverysystem like patches.

For oral administration, the allosteric modulators of mGluR4 thereof canbe combined with a suitable solid or liquid carrier or diluent to formcapsules, tablets, pills, powders, syrups, solutions, suspensions andthe like.

The tablets, pills, capsules, and the like contain from about 0.01 toabout 99 weight percent of the active ingredient and a binder such asgum tragacanth, acacias, corn starch or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid, a lubricant such as magnesium stearate; and asweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

For parenteral administration the disclosed allosteric modulators ofmGluR4 can be combined with sterile aqueous or organic media to forminjectable solutions or suspensions. For example, solutions in sesame orpeanut oil, aqueous propylene glycol and the like can be used, as wellas aqueous solutions of water-soluble pharmaceutically-acceptable saltsof the compounds. Dispersions can also be prepared in glycerol, liquidpolyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

In addition, to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation, for example, subcutaneously orintramuscularly or by intramuscular injection. Thus, for example, as anemulsion in an acceptable oil, or ion exchange resins, or as sparinglysoluble derivatives, for example, as sparingly soluble salts.

Preferably disclosed allosteric modulators of mGluR4 or pharmaceuticalformulations containing these compounds are in unit dosage form foradministration to a mammal. The unit dosage form can be any unit dosageform known in the art including, for example, a capsule, an IV bag, atablet, or a vial. The quantity of active ingredient in a unit dose ofcomposition is an effective amount and may be varied according to theparticular treatment involved. It may be appreciated that it may benecessary to make routine variations to the dosage depending on the ageand condition of the patient. The dosage will also depend on the routeof administration which may be by a variety of routes including oral,aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular,intraperitoneal and intranasal.

Methods of Synthesis

The compounds according to the invention, in particular the compoundsaccording to the Formula (I), may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (Green T. W. and Wuts P. G. M., (1991) ProtectingGroups in Organic Synthesis, John Wiley & Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprocess as well as the reaction conditions and order of their executionshall be consistent with the preparation of compounds of Formula (I).

The compounds according to the invention may be represented as a mixtureof enantiomers, which may be resolved into the individual pure R- orS-enantiomers. If for instance, a particular enantiomer is required, itmay be prepared by asymmetric synthesis or by derivation with a chiralauxiliary, where the resulting diastereomeric mixture is separated andthe auxiliary group cleaved to provide the pure desired enantiomers.Alternatively, where the molecule contains a basic functional group suchas an amino or an acidic functional group such as carboxyl, thisresolution may be conveniently performed by fractional crystallizationfrom various solvents as the salts of an optical active acid or by othermethods known in the literature (e.g. chiral column chromatography).

Resolution of the final product, an intermediate or a starting materialmay be performed by any suitable method known in the art (Eliel E. L.,Wilen S. H. and Wilder L. N., (1984) Stereochemistry of OrganicCompounds, Wiley-Interscience).

Many of the heterocyclic compounds of the invention can be preparedusing synthetic routes well known in the art (Katrizky A. R. and Rees C.W., (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).

The product from the reaction can be isolated and purified employingstandard techniques, such as extraction, chromatography, crystallizationand distillation.

The compounds of the invention may be prepared by general route ofsynthesis as disclosed in the following methods.

In one embodiment of the present invention compounds of Formula (I) maybe prepared according to the synthetic sequences illustrated inScheme 1. Pyrazole g1 can be protected (PG: protecting group), forexample by p-methoxybenzyl using standard conditions. Then amidine g4can be synthesized from ester g2 treated with aluminium chloride in thepresence of ammonium chloride. The subsequent cyclization reactionbetween amidine g4 and trichloromethyl hypochlorothioite g3 may beperformed in the presence of sodium hydroxide. The resultingchlorothiadiazole g5 can be substituted by alcohol such as MOH in thepresence of a base such as silver carbonate and then be deprotected inthe presence of TFA when PG is p-methoxybenzyl. Finally, compound g7 canbe alkylated, acylated or sulfonylated using conditions well known forpeople skilled in the art.

In one embodiment of the present invention, the compounds of Formula (I)may be prepared according to the synthetic sequences illustrated inScheme 2. Hydrolysis of ester g2 and formation of the bromoketone g9,was carried out via the acid chloride and consequently the diazoketone.Substitution of bromide by thiocyanate can furnish compound g10 whichcan be cyclized under acidic conditions to yield hydroxythiazole g11.Compound g11 can be coupled to a ring such as MX, in the presence ofcopper and a base such as cesium carbonate, and then be deprotected inthe presence of TFA when PG is p-methoxybenzyl. Finally, compound g13can be alkylated, acylated or sulfonylated using conditions well knownfor people skilled in the art.

In one embodiment of the present invention, the compounds of Formula (I)may be prepared according to the synthetic sequences illustrated inScheme 3. Dibromothiazole g16 can be monosubstituted by MOH, in thepresence of a base such as silver carbonate or potassium carbonate toyield g17, which can be subjected to Suzuki coupling with the protectedpyrazole g15. Standard deprotection under acidic conditions, when PG isp-methoxybenzyl can lead to compound g13 which can finally be alkylated,acylated or sulfonylated using conditions well known for people skilledin the art.

In one embodiment of the present invention, the compounds of Formula (I)may be prepared according to the synthetic sequences illustrated inScheme 4. Suzuki coupling, as described above, can also be done with nonprotected boronic esters or acids g14, to yield compound g13 which canfinally be alkylated, acylated or sulfonylated using conditions wellknown for people skilled in the art.

In one embodiment of the present invention, the compounds of Formula (I)may be prepared according to Scheme 5. The carboxylic acid moiety g18was treated with oxalyl chloride and then with N,O-dimethylhydroxylaminehydrochloride to yield the Weinreb amide g19. After iodination, in thepresence of iodine, the resulting compound g21 can be coupled usingSuzuki coupling conditions with boronic esters or acids g20 to yieldether g22. Weinreb amide g22 can undergo a Grignard reaction addition toyield ketone g23. The final product g24 can be easily obtained bydeprotection of the pyrazole in the presence of TFA, and can bealkylated, acylated or sulfonylated using conditions well known forpeople skilled in the art.

In one embodiment of the present invention, the compounds of Formula (I)may be prepared according to the synthetic sequences illustrated inScheme 6. Bromoketone g26, as described above, can be subjected to thecyclisation in the presence of thiourea to yield aminothiazole g27 whichcan be chlorinated in the presence of NCS to yield compound g28. Theresulting 2-aminothiazole g28 can be transformed into 2-bromothiazoleg29 using standard Sandmeyer conditions. g29 is subsequently coupled toMOH via substitution and finally deprotected under classical conditionsto yield g31 which can be alkylated, acylated or sulfonylated usingconditions well known for people skilled in the art.

In one embodiment of the present invention, the compounds of Formula (I)may be prepared according to the synthetic sequences illustrated inScheme 7. Ester g32 can be subjected to the addition of(cyanomethyl)lithium in order to afford 1,3-cyanocarbonyl compound g33which can undergo easy bromination, in to presence of cupric bromide.Cyclisation may be performed with thiourea and the resulting2-aminothiazole g35 can be transformed into 2-bromothiazole g36 usingstandard Sandmeyer conditions. After substitution of g36 by MOH underbasic conditions, g37 is subsequently deprotected under classicalconditions to yield g38 which can be alkylated, acylated or sulfonylatedusing conditions well known for people skilled in the art.

Experimental

Unless otherwise noted, all starting materials were obtained fromcommercial suppliers and used without further purification.

Specifically, the following abbreviations may be used in the examplesand throughout the specification.

Ag₂O (Silver monoxide) BuLi (Butyl lithium) tert-BuONO(tert-Butylnitrite) CHCl₃ (Chloroform) CuBr₂ (Copper (II) bromide) DCM(Dichloromethane) DMF (Dimethylformamide) EtOAc (Ethyl acetate) EtOH(Ethanol) Et₂O (Diethyl ether) Et₃N (Triethylamine) HBr (Hydrobromicacid) HCl (Hydrochloric acid) I (Iodine) K₂CO₃ (Potassium carbonate)LCMS (Liquid Chromatography Mass Spectrum) M (Molar) MeOH (Methanol) mg(Milligrams) MgSO₄ (Magnesium sulfate) μL (Microliters) mL (Milliliters)mmol (Millimoles) M.p. (Melting point) NCS (N-Chlorosuccinimide) NH₃(Ammonia) NH₄Cl (Ammonium chloride) NaHCO₃ (Sodium hydrogenocarbonate)NaOH (Sodium hydroxide) Na₂CO₃ (Sodium carbonate) Na₂SO₃ (Sodiumsulfite) Na₂SO₄ (Sodium sulfate) PE (Petroleum ether) PdCl₂(dppf)(1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride) PMBCl(p-Methoxybenzylchloride) RT (Retention Time) TFA (Trifluoroacetic acid)THF (Tetrahydrofuran) TMSCHN₂ (Trimethylsilyldiazomethane) UPLC-MS(Ultra Performance Liquid Chromatography Mass Spectrum)

All references to brine refer to a saturated aqueous solution of NaCl.Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions are conducted not under an inertatmosphere at room temperature unless otherwise noted.

Most of the reactions were monitored by thin-layer chromatography on0.25 mm Merck silica gel plates (60E-254), visualized with UV light.Flash column chromatography was performed on prepacked silica gelcartridges (15-40 μM, Merck).

Melting point determination was performed on a Buchi B-540 apparatus.

LC-MS and HPLC-MS Methods:

LC-MS Methods

a) Reversed phase HPLC was carried out on an Zorbax SB-C18 cartridge(1.8 μm, 4.6×30 mm) from Agilent, with a flow rate of 1.5 mL/min. Thegradient conditions used are: 90% A (water+0.05% of formic acid), 10% B(acetonitrile+0.05% of formic acid) to 100% B at 3.5 minutes, kept till3.7 minutes and equilibrated to initial conditions at 3.8 minutes until4.5 minutes. Injection volume 5-20 μL. ES MS detector was used,acquiring both in positive and negative ionization modes. Cone voltagewas 30 V for both positive and negative ionization modes.

b) LC-MS were recorded on Agilent 1200 RRLC equipped with 6110 MSD withthe following conditions: Reversed phase HPLC was carried out on ZorbaxSB-C18 analytical column (5 μm, 2.1×50 mm) from Agilent, with a flowrate of 0.8 mL/min. The gradient conditions used are: 90% A (water+0.1%of trifluoroacetic acid), 10% B (acetonitrile+0.05% of trifluoroaceticacid) to 100% B at 3.5 minutes, kept till 4.0 minutes and equilibratedto initial conditions at 4.01 minutes until 4.5 minutes. Injectionvolume 2-5 μL. ES MS detector was used, acquiring in positive ionizationmode.

UPLC-MS Method

UPLC-MS were recorded on Waters ACQUITY UPLC with the followingconditions: Reversed phase HPLC was carried out on BEH-C18 cartridge(1.7 μm, 2.1×50 mm) from Waters, with a flow rate of 0.8 mL/min. Thegradient conditions used are: 90% A (water+0.1% of formic acid), 10% B(acetonitrile+0.1% of formic acid) to 100% B at 1.3 minutes, kept till1.6 minutes and equilibrated to initial conditions at 1.7 minutes until2.0 minutes. Injection volume 5 μL. ES MS detector was used, acquiringboth in positive and negative ionization modes.

All mass spectra were taken under electrospray ionisation (ESI) methods.

Preparative HPLC was conducted using a Gilson GX-281 preparative HPLC(322 Binary Gradient Module, 156 UV/Visible detector GX-281injector/fraction collector) Phenomenex Synergi Max-Rp (C₁₂, 30×150 mm,4 μm) or Kromasil Eternity (C₁₈, 30×150 mm, 5 μm) columns and H₂O+0.1%TFA and CH₃CN as eluents. Gradients used cover the range from 0% CH₃CNto 100% CH₃CN.

¹H-NMR spectra were recorded on a Bruker Avance (400 MHz, 300 MHz) orVarian 400 MHz spectrometer. Chemical shifts are expressed in parts permillion (ppm, δ units). Coupling constants are in units of hertz (Hz)Splitting patterns describe apparent multiplicities and are designatedas s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet),br (broad).

EXAMPLES Example 15-(Pyridin-2-yloxy)-3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazole(Final Compound 1.2) Ethyl1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate

According to Scheme 1, Step 1: K₂CO₃ (11.5 mmol, 1.59 g) was added to asolution of ethyl 5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (7.69mmol, 1.60 g) in acetonitrile (24 mL) followed by1-(chloromethyl)-4-methoxybenzene (8.46 mmol, 1.15 mL) and the reactionmixture was heated under reflux for 4.5 hours. After evaporation of thesolvent, the reaction mixture was diluted with brine and EtOAc. Theaqueous phase was extracted with EtOAc. The organic phase was dried overMgSO₄, was filtered and was concentrated under reduced pressure to yieldethyl 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate(7.68 mmol, 2.52 g, 100%) as an oil.

UPLC-MS: RT=0.56 min; MS m/z ES⁺=329.

1-(4-Methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboximidamide

According to Scheme 1, Step 2: Trimethylaluminium, 2M solution inheptane (198 mmol, 99 mL), was added dropwise to a suspension of NH₄Cl(198 mmol, 10.6 g) in dry toluene (150 mL), under an argon atmosphere,at −5° C. The reaction mixture was stirred at room temperature until nomore evolution of gas was observed. After addition of a mixture of ethyl1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (19.8mmol, 6.50 g) in toluene (25 mL) at 0° C., the reaction mixture wasstirred at 80° C. for 16 hours. The reaction mixture was then cooleddown to 0° C. and MeOH (200 mL) was added with consequent stirring for 1hour at room temperature. After filtration and concentration of thesolvent, the residue was purified by flash chromotagraphy over silicagel using CHCl₃/MeOH (80:20) as eluent to yield1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboximidamide(18.8 mmol, 5.6 g, 95%) as a white solid.

5-Chloro-3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazole

According to Scheme 1, Step 3: NaOH (3.94 mmol, 158 mg) in water (4 mL)was added dropwise, at −5° C., to a solution of1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboximidamide(1.68 mmol, 500 mg) and trichloromethyl hypochlorothioite (1.68 mmol,183 μL) in DCM (6 mL). The reaction mixture was stirred for 30 minutesat 0° C. and then 3 days at room temperature. After dilution with water,a saturated solution of Na₂CO₃ and DCM, the aqueous phase was extractedwith DCM. The organic phase was dried over MgSO₄, was filtered and wasevaporated. The resulting crude product was purified by flashchromatography over silica gel using cyclohexane/EtOAc (90:10) as eluentto yield5-chloro-3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazole (0.43mmol, 160 mg, 25%) as a yellow oil.

UPLC-MS: RT=1.21 min; MS m/z ES⁺=375.

3-(1-(4-Methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yloxy)-1,2,4-thiadiazole

According to Scheme 1, Step 4: Pyridin-2-ol (0.32 mmol, 30.5 mg) andsilver carbonate (0.38 mmol, 106 mg) were added to a solution of5-chloro-3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazole (0.32mmol, 120 mg) in acetonitrile (2 mL) and the reaction mixture wasstirred for 45 minutes at 180° C. After filtration through celite andevaporation of the solvent, the resulting crude product was purified byflash chromatography over silica gel using cyclohexane/EtOAc (90:10) aseluent to yield3-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yloxy)-1,2,4-thiadiazole(0.15 mmol, 65 mg, 47%) as a yellow oil.

UPLC-MS: RT=1.21 min; MS m/z ES⁺=434.

5-(Pyridin-2-yloxy)-3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazole

According to Scheme 1, Step 5: Trifluoromethanesulfonic acid (1.80 mmol,0.17 mL) was added to a solution of3-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yloxy)-1,2,4-thiadiazole(0.15 mmol, 65 mg) in TFA (4 mL) and the reaction mixture was stirredfor 8 minutes at 80° C. The crude residue was neutralized with asaturated solution of Na₂CO₃ and the aqueous phase was extracted withEtOAc. The organic phase was dried over MgSO₄, was filtered and wasconcentrated. The crude residue was purified by flash chromatographyover silica gel using DCM/MeOH (98:2 to 95:5) as eluent to yield afterevaporation5-(pyridin-2-yloxy)-3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazole(43 μmol, 14 mg, 29%) as a yellow solid.

M.p.: 245-247° C.;

UPLC-MS: RT=0.91 min; MS m/z ES⁺=314;

¹H-NMR (300 MHz, DMSO): 8.60 (s, 1H), 8.53-8.50 (dd, 1H), 8.19-8.12 (m,1H), 7.59-7.53 (d, 1H), 7.52-7.44 (m, 1H).

Example 2 4-(5-Methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yloxy)thiazole(Final Compound 1.4)1-(4-Methoxybenzyl)-3-methyl-1H-pyrazole-4-carboxylic acid

According to Scheme 2, Step 1: A solution of NaOH 3 M (108 mmol, 35.8mL) was added slowly, at 0° C., to a solution of ethyl1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carboxylate (43 mmol, 11.8 g)in MeOH (108 mL) and the reaction mixture was heated at 50° C. for 2hours. After evaporation of the solvent, the residue was partitionedbetween a NaOH 1M solution and Et₂O. The organic layer was washed with aNaOH 1M solution. The aqueous layer was acidified to pH=1-2 with a HCl1M solution and the aqueous phase was extracted with DCM. The organicphase was dried over Na₂SO₄, was filtered and was concentrated underreduced pressure to yield1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carboxylic acid (37.8 mmol,9.30 g, 88%) as a beige solid. The crude product was used without anypurification.

UPLC-MS: RT=0.70 min; MS m/z ES⁺=247.

2-Bromo-1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)ethanone

According to Scheme 2, Step 2: To a solution of1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carboxylic acid (37.8 mmol,9.30 g) and five drops of DMF in DCM (94 mL) was added oxalyl chloride(76 mmol, 6.66 mL) dropwise, at 0° C. The reaction mixture was allowedto warm up to room temperature and was stirred for 3 hours. Afterconcentration, the residue was treated with toluene and wasco-evaporated to dryness to yield1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carbonyl chloride. To asolution of 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carbonyl chloride(37.8 mmol) in acetonitrile (94 mL) was added a solution of TMSCHN₂(41.5 mmol, 83.0 mL) dropwise, at 0° C., and then the reaction mixturewas allowed to warm up to room temperature and was stirred overnight.After cooling the reaction mixture to −10° C., HBr 48% (14.8 mL) wasadded dropwise and the reaction mixture was stirred for 2 hours at −10°C. At 0° C., 10% NaOH solution was added to the reaction mixture toreach pH=7. The reaction mixture was diluted with water and EtOAc andthe aqueous phase was extracted with EtOAc. The organic phase was driedover MgSO₄, was filtered and was concentrated under reduced pressure toyield 2-bromo-1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)ethanone(30.6 mmol, 9.90 g, 81%) which was used without any purification.

UPLC-MS: RT=0.86 min; MS m/z ES⁺=323, 325.

1-(1-(4-Methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-thiocyanatoethanone

According to Scheme 2, Step 3: To a solution of2-bromo-1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)ethanone (9.28mmol, 3.00 g) in acetone (19 mL) was added potassium thiocyanate (9.28mmol, 0.90 g) and the reaction mixture was stirred overnight at roomtemperature. Then, the reaction mixture was diluted with EtOAc and theorganic phase was washed with water. The organic phase was dried overMgSO₄, was filtered and was concentrated. The crude residue was purifiedby flash chromatography over silica gel using cyclohexane/EtOAc (80:20to 50:50) as eluent to yield1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-thiocyanatoethanone(6.57 mmol, 1.98 g, 71%).

UPLC-MS: RT=0.88 min; MS m/z ES⁺=302.

4-(1-(4-Methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)thiazol-2-ol

According to Scheme 2, Step 4: To a solution of1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-thiocyanatoethanone(6.57 mmol, 1.98 g) in EtOH was added HCl concentrated (1 mL) and thereaction mixture was stirred under reflux for 8 hours. After cooling toroom temperature, the solvent was removed under reduced pressure and theresidue was diluted with water. The aqueous phase was basified with NaOHand was extracted with DCM. The organic phase was dried over MgSO₄, wasfiltered and was evaporated. The crude residue was purified by flashchromatography over silica gel using DCM/EtOH/NH₃ (100:0:0 to95:4.5:0.5) as eluent to yield4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)thiazol-2-ol (3.42 mmol,1.03 g, 52%).

UPLC-MS: RT=0.76 min; MS m/z ES⁺=302.

4-(1-(4-Methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yloxy)thiazole

According to Scheme 2, Step 5: A mixture of4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)thiazol-2-ol (0.99 mmol,300 mg), 2-chloropyrimidine (0.99 mmol, 114 mg), copper (0.20 mmol, 12.6mg) and cesium carbonate (2.99 mmol, 973 mg) in DMF (3.3 mL) was stirredat 160° C. under microwave conditions for 45 minutes. Then, the reactionmixture was diluted with EtOAc and was washed with water. The organicphase was dried over MgSO₄, was filtered and was evaporated. The crudemixture was purified by flash chromatography over silica gel usingcyclohexane/EtOAc (80:20 to 60:40) as eluent to yield4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yloxy)thiazole(0.18 mmol, 67 mg, 18%) as a yellow oil.

UPLC-MS: RT=0.92 min; MS m/z ES⁺=380.

4-(5-Methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yloxy)thiazole

According to Scheme 2, Step 6: To a solution of4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yloxy)thiazole(0.18 mmol, 67 mg) in TFA (1.8 mL) was added trifluoromethanesulfonicacid (1.77 mmol, 156 μl). The reaction mixture was stirred for 8 minutesat 80° C. under microwave conditions. The crude mixture was quenchedwith water and the aqueous phase was extracted with DCM. The organiclayer was dried over MgSO₄, was filtered and was evaporated to dryness.The crude residue was purified by preparative TLC using DCM/EtOH/NH₃(100:0:0 to 93:6.7:0.3) as eluent to yield4-(5-methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yloxy)thiazole (12 μmol, 3.2mg, 7%) as a beige solid.

M.p.: 177° C.;

UPLC-MS: RT=0.60 min; MS m/z ES⁺=260;

¹H-NMR (300 MHz, MeOD): 8.78 (d, J=5.0 Hz, 2H), 7.85 (s, 1H), 7.45-7.35(m, 1H), 7.15 (s, 1H), 2.48 (s, 3H).

Example 3 4-(1H-Pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole (FinalCompound 1.6)1-(4-Methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

According to Scheme 3, Step 1: The compound was synthesized with thesame procedure as used in Example 1, Step 1 (23.8 mmol, 7.47 g, 91%).

UPLC-MS: RT=1.02 min; MS m/z ES⁺=315.

2-(4-Bromothiazol-2-yloxy)pyridine

According to Scheme 3, Step 2: Pyridin-2-ol (4.12 mmol, 0.39 g) and thensilver carbonate (4.94 mmol, 1.36 g) were added to a solution of2,4-dibromothiazole (4.12 mmol, 1.00 g) in DMF (18 mL) and the reactionmixture was heated at 140° C. overnight. After evaporation of thesolvent, the reaction mixture was dissolved in DCM and was filteredthrough celite. The organic phase was washed with water, was dried overMgSO₄, was filtered and was concentrated under reduced pressure to yield2-(4-bromothiazol-2-yloxy)pyridine (1.56 mmol, 400 mg, 34%).

UPLC-MS: RT=0.97 min; MS m/z ES⁺=257, 259.

2-(4-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yloxy)pyridine

According to Scheme 3, Step 3: A mixture of2-(4-bromothiazol-2-yloxy)pyridine (1.56 mmol, 400 mg),1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.87 mmol, 587 mg), PdCl₂(dppf) (0.16 mmol, 127 mg) andN-ethyl-N-isopropylpropan-2-amine (3.11 mmol, 0.53 mL) in dioxane/water(1:1, 10 mL) was stirred at 150° C. for 1 hour under microwaveconditions. The reaction mixture was filtered through a pad of celiteand was washed with DCM. The organic phase was washed with water, wasdried over MgSO₄, was filtered and was concentrated under reducedpressure. The crude mixture was purified by flash chromatography oversilica gel using cyclohexane/EtOAc (90:10 to 70:30) as eluent to yield2-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yloxy)pyridine (0.23mmol, 83 mg, 9%) as an oil.

UPLC-MS: RT=1.02 min; MS m/z ES⁺=365.

4-(1H-Pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole

According to Scheme 3, Step 4: The compound was synthesized with thesame procedure as used in Example 2, Step 6 and was obtained as a beigesolid (70 μmol, 17 mg, 31%).

M.p.: 151-152° C.;

UPLC-MS: RT=0.71 min; MS m/z ES⁺=245;

¹H-NMR (300 MHz, DMSO): 8.37-8.35 (m, 1H), 8.05-7.99 (m, 2H), 7.37-7.32(m, 3H).

Example 44-(3-Methyl-1H-pyrazol-4-yl)-2-(6-methylpyridin-2-yloxy)thiazole (FinalCompound 1.11)

According to Scheme 4: A mixture of2-(4-bromothiazol-2-yloxy)-6-methylpyridine (0.37 mmol, 100 mg),3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.44 mmol, 92 mg), Pd (dppf) (37 μmol, 30 mg) andN-ethyl-N-isopropylpropan-2-amine (0.74 mmol, 0.13 mL) in dioxane/water(1:1, 2.5 mL) was stirred at 120° C. for 1 hour under microwaveconditions. To complete the reaction, PdCl₂(dppf) (37 μmol, 30 mg) and3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.44 mmol, 92 mg) were added and the reaction mixture was stirred at120° C. for 1.5 hour under microwave conditions. The reaction mixturewas filtered through a pad of celite and was washed with DCM. Theorganic phase was washed with water, was dried over MgSO₄, was filteredand was concentrated under reduced pressure. The crude mixture waspurified by flash chromatography over silica gel using DCM/EtOH/NH₃(100:0:0 to 93:6.4:0.6) as eluent to yield4-(3-methyl-1H-pyrazol-4-yl)-2-(6-methylpyridin-2-yloxy)thiazole (95μmol, 26 mg, 26%) as an orange solid.

M.p.: 138-139° C.;

UPLC-MS: RT=0.85 min; MS m/z ES⁺=273;

¹H-NMR (300 MHz, DMSO): 7.84 (s, 1H), 7.80-7.76 (m, 1H), 7.14 (d, J=8.0Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.01 (s, 1H), 2.54 (s, 3H), 2.47 (s,3H).

Example 51-(4-(2-(6-Methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazol-3-yl)ethanone(Final Compound 1.9)1-(4-Methoxybenzyl)-N-methoxy-N-methyl-1H-pyrazole-5-carboxamide and1-(4-methoxybenzyl)-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide

According to Scheme 5, Step 1: Oxalyl chloride (63.9 mmol, 5.49 mL)followed by few drops of DMF were added to a solution of1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylic acid and1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylic acid (31.9 mmol, 7.42 g) inDCM (128 mL). When no more gas was generated, the solution wasevaporated to dryness and then the residue was diluted in DCM (150 mL).The resulting acid chloride solution was added to a solution ofN,O-dimethylhydroxylamine hydrochloride (35.1 mmol, 3.43 g) and Et₃N(80.0 mmol, 11.2 mL) in dry DCM (50 mL), under nitrogen, at 0° C. Thereaction mixture was stirred at room temperature for 2 hours. Then thereaction mixture was diluted with DCM and was washed with water, 1M HClcold solution, 1M NaOH solution and brine. The combined organic phaseswere dried over MgSO₄, filtered and evaporated to dryness. The crudemixture was purified by flash chromatography over silica gel usingcyclohexane/EtOAc (90:10 to 50:50) as eluent to yield a mixture of1-(4-methoxybenzyl)-N-methoxy-N-methyl-1H-pyrazole-5-carboxamide and1-(4-methoxybenzyl)-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide (25.8mmol, 7.10 g, 81%) as a yellow oil.

UPLC-MS: RT=0.75 and 0.80 min; MS m/z ES⁺=276.

1-(4-Methoxybenzyl)-4-iodo-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide

According to Scheme 5, Step 2: I₂ (7.99 mmol, 2.03 g) followed bydiammonium cerium(IV) nitrate (16.0 mmol, 8.76 g) were added to asolution of1-(4-methoxybenzyl)-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide (16.0mmol, 4.40 g) in acetonitrile (80 mL). The reaction mixture was stirredat room temperature for 12 hours. Na₂SO₃ was added, the reaction mixturewas stirred for 30 minutes and then, the reaction mixture was filteredthrough a pad of celite. The filtrate was extracted with EtOAc, theorganic phase was dried over MgSO₄, was filtered and was evaporated todryness. The crude mixture was purified by flash chromatography oversilica gel using cyclohexane/EtOAc (90:10 to 60:40) as eluent andanother flash chromatography over C₁₈ using acetonitrile/water (20:80 to50:50) to yield1-(4-methoxybenzyl)-4-iodo-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide(4.09 mmol, 1.64 g, 26%) as a colorless oil.

UPLC-MS: RT=0.89 min; MS m/z ES⁺=402.

2-(6-Methylpyridin-2-yloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole

According to Scheme 5, Step 3: At −78° C., under a nitrogen atmosphere,BuLi (3.69 mmol, 1.48 mL) was added dropwise to a solution of2-(4-bromothiazol-2-yloxy)-6-methylpyridine (1.68 mmol, 455 mg) in Et₂O(17 mL). After 5 minutes of stirring at −78° C.,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.69 mmol, 0.75mL) was added and the resulting mixture was stirred at room temperaturefor 20 minutes. The reaction was quenched with a NH₄Cl saturated aqueoussolution and was extracted with EtOAc. The combined organic phases weredried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude mixture was purified by flash chromatography over silica gel usingcyclohexane/EtOAc (70:30 to 30:70) as eluent to yield2-(6-methylpyridin-2-yloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole(0.49 mmol, 157 mg, 29%).

UPLC-MS: RT=0.68 min; MS m/z ES⁺=236.

1-(4-Methoxybenzyl)-N-methoxy-N-methyl-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazole-3-carboxamide

According to Scheme 5, Step 4: A mixture of1-(4-methoxybenzyl)-4-iodo-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide(0.59 mmol, 238 mg),2-(6-methylpyridin-2-yloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole(0.49 mmol, 157 mg), PdCl₂(dppf) (49 μmol, 40 mg) andN-ethyl-N-isopropylpropan-2-amine (0.99 mmol, 0.17 mL) in dioxane/water(1:1, 3.3 mL) was stirred at 120° C. for 30 minutes under microwaveconditions. The reaction mixture was filtered through a pad of celiteand was washed with DCM. The organic phase was washed with water, wasdried over MgSO₄, was filtered and was concentrated under reducedpressure. The crude mixture was purified by flash chromatography oversilica gel using cyclohexane/EtOAc (90:10 to 70:30) as eluent to yield1-(4-methoxybenzyl)-N-methoxy-N-methyl-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazole-3-carboxamide(99 μmol, 46 mg, 15%) as an oil.

UPLC-MS: RT=1.06 min; MS m/z ES⁺=466.

1-(1-(4-Methoxybenzyl)-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazol-3-yl)methanone

According to Scheme 5, Step 5: Methylmagnesium bromide 3 M (148 μmol, 49μL) was added dropwise at room temperature to a solution of1-(4-methoxybenzyl)-N-methoxy-N-methyl-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazole-3-carboxamide(99 μmol, 46 mg) in THF (0.5 mL) and the reaction mixture was stirredfor 1 hour at room temperature. The reaction was diluted with EtOAc andwith an aqueous solution of HCl 1M. The aqueous phase was extracted withEtOAc. The organic phase was dried over Na₂SO₄, was filtered and wasconcentrated to yield1-(1-(4-methoxybenzyl)-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazol-3-yl)ethanone(0.10 mmol, 42 mg, 100%) as a beige solid. The mixture was used withoutfurther purification.

UPLC-MS: RT=1.26 min; MS m/z ES⁺=321.

1-(4-(2-(6-Methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazol-3-yl)ethanone

According to Scheme 5, Step 6: The compound was synthesized with thesame procedure as used in Example 2, Step 6 and was obtained as a whitesolid (19 μmol, 5.8 mg, 19%).

M.p.: 194-195° C.;

UPLC-MS: RT=0.94 min; MS m/z ES⁺=301;

¹H-NMR (300 MHz, DMSO): 8.26 (s, 1H), 8.09 (s, 1H), 7.91-7.87 (m, 1H),7.21 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 2.60 (s, 3H), 2.51 (s,3H).

Example 6 5-Chloro-4-(1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole(Final Compound 1.19)4-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-amine

According to Scheme 6, Step 1: A solution of1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-bromoethanone (9.70 mmol, 3.00g) and of thiourea (9.70 mmol, 739 mg) in acetone (20 mL) was stirredunder reflux for 1 hour. After filtration and evaporation of thefiltrate, the white solid was partitioned between EtOAc and a saturatedsolution of Na₂CO₃. The aqueous phase was extracted with EtOAc. Theorganic phase was dried over Na₂SO₄, was filtered and was concentratedto yield 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-amine (8.14mmol, 2.33 g) as an orange foam.

UPLC-MS: RT=0.57 min; MS m/z ES⁺=287.

4-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-5-chlorothiazol-2-amine

According to Scheme 6, Step 2: NCS (8.14 mmol, 1.09 g) was added to asolution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-amine (8.14mmol, 2.33 g) in acetonitrile (20 mL) and the reaction mixture wasstirred under reflux for 1.5 hour. After evaporation of the solvent, thecrude residue was diluted in EtOAc. The organic phase was washed withwater and brine, was dried over Na₂SO₄, was filtered and wasconcentrated. The crude mixture was purified by flash chromatographyover silica gel using DCM/MeOH (100:0 to 90:10) as eluent to yield4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-chlorothiazol-2-amine (2.35mmol, 755 mg, 29%).

1-(4-Methoxybenzyl)-4-(2-bromo-5-chlorothiazol-4-yl)-1H-pyrazole

According to Scheme 6, Step 3: To a solution of4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-chlorothiazol-2-amine (2.35mmol, 755 mg) in acetonitrile (12 mL) were added tert-BuONO (2.59 mmol,267 mg) and CuBr₂ (2.59 mmol, 578 mg) and the reaction mixture wasstirred at 90° C. for 1 hour. After cooling to room temperature, thesolvent was removed under reduced pressure. The crude mixture waspurified by flash chromatography over silica gel using cyclohexane/EtOAc(90:10) as eluent to yield1-(4-methoxybenzyl)-4-(2-bromo-5-chlorothiazol-4-yl)-1H-pyrazole (1.04mmol, 400 mg, 44%) as a brown oil.

UPLC-MS: RT=1.22 min; MS m/z ES⁺=384, 386.

2-(4-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-5-chlorothiazol-2-yloxy)pyridine

According to Scheme 6, Step 4: The compound was synthesized with thesame procedure as used in Example 3, Step 2 and was obtained as a whitesolid (60 μmol, 24 mg, 20%).

UPLC-MS: RT=1.21 min; MS m/z ES⁺=399, 401.

5-Chloro-4-(1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole

According to Scheme 6, Step 5: The compound was synthesized with thesame procedure as used in Example 1, Step 5 and was obtained as a whitesolid (20 mot, 5.6 mg, 40%).

UPLC-MS: RT=0.90 min; MS m/z ES⁺=279;

¹H-NMR (300 MHz, CDCl₃): 8.32-8.28 (m, 1H), 8.23 (bs, 2H), 7.82-7.78 (m,1H), 7.18-7.14 (m, 2H).

Example 7 4-(1H-Pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile(Final Compound 1.20)3-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile

According to Scheme 7, Step 1: At −78° C., BuLi (23 mmol, 9.2 mL, 2.5M)was added dropwise to a solution of acetonitrile (21.1 mmol, 0.87 g) inTHF (25 mL). The resulting mixture was stirred at this temperature for20 minutes and then ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate(19.2 mmol, 5.00 g) in THF (25 mL) was added. The reaction mixture wasstirred at −78° C. for 1 hour and then allowed to warm up to roomtemperature and stirred for another 1 hour. The reaction was quenchedwith saturated NH₄Cl aqueous solution and extracted with EtOAc (50mL×3). The combined organic phases were dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified oncombi-flash EtOAc/PE (1:15 to ˜1:5) to give3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile (13.1 mmol,3.33 g, 68%).

¹H-NMR (300 MHz, DMSO): δ 8.62 (s, 1H), 8.05 (s, 1H), 7.32 (s, 1H), 6.97(d, J=7.0 Hz, 2H), 5.36 (s, 1H), 4.51 (s, 1H), 3.79 (s, 1H).

2-Bromo-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile

According to Scheme 7, Step 2: A suspension of3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile (33.7 mmol,8.60 g) and CuBr₂ (67.4 mmol, 15.0 g) in a mixture of THF/EtOAc/CHCl₃(150 mL/20 mL/20 mL) was stirred at reflux for 3 hours. After cooling toroom temperature, the mixture was filtered and the green filtrate waswashed with water. The organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified oncombi-flash EtOAc/PE (1:15 to ˜1:5) to give2-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile(25.3 mmol, 8.44 g, 75%).

LC-MS: m/z ES⁺=334, 336.

2-Amino-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-5-carbonitrile

According to Scheme 7, Step 3: To a solution of2-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile(25.3 mmol, 8.44 g) in EtOH (120 mL) was added thiourea (26.5 mmol, 2.06g). The resulting mixture was stirred at reflux for 2 hours. Aftercooling to room temperature, the solvent was removed under reducedpressure. The residue was purified by silica column on combi-flashEtOAc/PE (1:10 to ˜1:1) to give2-amino-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-5-carbonitrileas a yellow solid (22.0 mmol, 6.83 g, 87%).

LC-MS: m/z ES⁺=312.

2-Bromo-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-5-carbonitrile

According to Scheme 7, Step 4: To a solution of2-amino-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-5-carbonitrile(33.7 mmol, 10.5 g) in acetonitrile (100 mL) was added CuBr₂ (37.1 mmol,8.28 g) and tert-BuONO (40.5 mmol, 4.17 g). The resulting mixture wasstirred at room temperature for 30 minutes under nitrogen atmosphere andthen stirred at 70-80° C. for 1 hour. After cooling to room temperature,the mixture was filtered and concentrated under reduced pressure. Theresidue was purified by silica column on combi-flash EtOAc/PE (1:10 to˜1:1) to give2-bromo-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-5-carbonitrile(26.6 mmol, 9.99 g, 79%) as a brown solid.

LC-MS: m/z ES⁺=375, 377.

4-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile

According to Scheme 7, Step 5: To the reaction mixture of pyridin-2-ol(1.05 mmol, 100 mg) and2-bromo-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-5-carbonitrile(1.16 mmol, 434 mg) in dioxane (8 mL) was added Ag₂O (3.16 mmol, 733mg). The resulting mixture was stirred at reflux overnight. Aftercooling to room temperature, the mixture was filtered and concentratedunder reduced pressure. The residue was purified by preparative TLCPE/EtOAc (1:1) to give4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile(0.26 mmol, 153 mg, 37%) as a white solid.

LC-MS: m/z ES⁺=390.

4-(1H-Pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile

According to Scheme 7, Step 6: A solution of4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile(0.26 mmol, 153 mg) in TFA (5 mL) was stirred at 100° C. for 10 minutesunder microwave conditions. After cooling to room temperature, themixture was concentrated under reduced pressure. The residue was dilutedwith EtOAc and was washed with a saturated aqueous solution of NaHCO₃.The organic phase was dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by preparative HPLC to give4-(1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile as awhite solid (29 mg, 28%).

LC-MS: RT=2.79 min; MS m/z ES⁺=270;

¹H-NMR (400 MHz, MeOD): 8.36 (d, J=6.0 Hz, 1H), 7.99-7.97 (m, 2H),7.36-7.33 (m, 1H), 7.27 (d, J=8.0 Hz, 2H).

The compounds in the following Table have been synthesized according tothe same methods as previous examples 1 to 7, as denoted in the columndenoted as “Exp. nr”. The compounds denoted with the asterisk have beenexemplified in the Examples.

TABLE 1 Compounds prepared according to the Examples.

Co. nr. Exp nr.

X²—(A)_(m)

1-1 1

N

1-2* 1

N

1-3 1

N

1-4* 2

C—H

1-5 3

C—H

1-6* 3

C—H

1-7 3

C—H

1-8 3

C—H

1-9* 5

C—H

1-10 4

C—H

1-11* 4

C—H

1-12 3

C—H

1-13 3

C—H

1-14 4

C—H

1-15 4

C—H

1-16 4

C—H

1-17 5

C—H

1-18 3

C—H

1-19* 6

C—Cl

1-20* 7

C—CN

1-21 7

C—CN

TABLE 2 Physico-chemical data for some compounds (nd = not determined).Co. Nr M.p. (° C.) MW (theor) [MH⁺] RT (min) Method 1-1 165-166 258.30259 2.24 LC-MS a) 1-2 245-247 313.26 314 0.91 UPLC-MS 1-3 nd 347.70 3481.00 UPLC-MS 1-4 177 259.29 260 0.60 UPLC-MS 1-5 131-135 279.27 280 0.89UPLC-MS 1-6 151-152 244.27 245 0.71 UPLC-MS 1-7 158-161 292.74 293, 2950.88 UPLC-MS 1-8 160 276.29 277 0.79 UPLC-MS 1-9 194-195 300.34 301 0.94UPLC-MS 1-10 176-178 258.30 259 0.80 UPLC-MS 1-11 138-139 272.33 2730.85 UPLC-MS 1-12 nd 346.72 347 1.05 UPLC-MS 1-13 nd 312.27 313 0.94UPLC-MS 1-14 nd 249.33 250 1.01 UPLC-MS 1-15 nd 279.27 280 0.89 UPLC-MS1-16 nd 259.29 260 0.67 UPLC-MS 1-17 nd 321.30 322 1.00 UPLC-MS 1-18 nd262.26 263 0.75 UPLC-MS 1-19 nd 278.72 279 0.90 UPLC-MS 1-20 nd 269.28270 2.79 LC-MS b) 1-21 nd 303.73 304 2.97 LC-MS b)

TABLE 3 NMR-data Co. Nr NMR-data 1-1 ¹H-NMR (300 MHz, DMSO): 7.98 (s,1H), 7.61-7.42 (5H), 2.48 (s, 3H). 1-2 ¹H-NMR (300 MHz, DMSO): 8.60 (s,1H), 8.53-8.50 (dd, 1H), 8.19-8.12 (m, 1H), 7.59-7.53 (d, 1H), 7.52-7.44(m, 1H). 1-3 ¹¹H-NMR (300 MHz, DMSO): 8.61 (s, 1H), 8.22-8.16 (m, 1H),7.64-7.57 (m, 2H). 1-4 ¹H-NMR (300 MHz, MeOD): 8.78 (d, J = 5.0 Hz, 2H),7.85 (s, 1H), 7.45-7.35 (m, 1H), 7.15 (s, 1H), 2.48 (s, 3H). 1-5 ¹H-NMR(300 MHz, DMSO): 7.85 (s, 2H), 7.56-7.35 (m, 3H), 7.23 (s, 1H). 1-6¹H-NMR (300 MHz, DMSO): 8.37-8.35 (m, 1H), 8.05-7.99 (m, 2H), 7.37-7.32(m, 3H). 1-7 ¹H-NMR (300 MHz, MeOD): 7.94-7.90 (m, 1H), 7.83 (s, 1H),7.32 (d, J = 8 Hz, 1H), 7.20 (d, J = 8 Hz, 1H), 7.07 (s, 1H), 4.90 (s,3H). 1-8 ¹H-NMR (300 MHz, MeOD): 8.12 (dd, J = 1.5 Hz and 5 Hz, 1H),7.85-7.77 (m, 2H), 7.38-7.32 (m, 1H), 7.09 (s, 1H), 2.46 (s, 3H). 1-9¹H-NMR (300 MHz, DMSO): 8.26 (s, 1H), 8.09 (s, 1H), 7.91-7.87 (m, 1H),7.21 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 2.60 (s, 3H), 2.51(s, 3H). 1-10 ¹H-NMR (300 MHz, DMSO): 7.96 (s, 2H), 7.84-7.80 (m, 1H),7.16 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 2.54(s, 3H). 1-11 ¹H-NMR (300 MHz, DMSO): 7.84 (s, 1H), 7.80-7.76 (m, 1H),7.14 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 2.54(s, 3H), 2.47 (s, 3H). 1-12 ¹H-NMR (300 MHz, DMSO): 8.34 (s, 1H),8.11-8.05 (m, 1H), 7.54-7.48 (d, 1H), 7.43-7.39 (d, 1H), 7.38 (s, 1H).1-13 ¹H-NMR (300 MHz, DMSO): 8.40-8.35 (m, 1H), 8.32 (s, 1H), 8.07-7.98(m, 1H), 7.36-7.34 (m, 1H), 7.33 (s, 1H), 7.30 (s, 1H). 1-14 ¹H-NMR (300MHz, DMSO): 8.00 (s, 1H), 7.80 (s, 1H), 7.00 (s, 1H), 4.85-4.75 (m, 1H),2.05-1.95 (m, 2H), 1.70-1.20 (m, 8H). 1-15 ¹H-NMR (300 MHz, MeOD): 7.90(s, 1H), 7.52-7.48 (m, 1H), 7.22-7.18 (m, 1H), 7.12-7.08 (m, 2H), 7.00(s, 1H). 1-16 ¹H-NMR (300 MHz, MeOD): 8.45 (s, 1H), 8.40 (s, 1H), 8.00(d, 2H), 7.25 (s, 1H), 2.60 (s, 3H). 1-17 ¹H-NMR (300 MHz, CDCl₃): 7.95(s, 1H), 7.90 (s, 1H), 7.32-7.28 (m, 1H), 6.92-6.88 (m, 2H), 2.60 (s,3H). 1-18 ¹H-NMR (300 MHz, DMSO): 8.50 (d, 1H), 8.05-7.95 (m, 2H), 7.00(dd, 2H), 6.90 (s, 1H). 1-19 ¹H-NMR (300 MHz, CDCl₃): 8.32-8.28 (m, 1H),8.23 (bs, 2H), 7.82-7.78 (m, 1H), 7.18-7.14 (m, 2H). 1-20 ¹H-NMR (400MHz, MeOD): 8.36 (d, J = 6.0 Hz, 1H), 7.99-7.97 (m, 2H), 7.36-7.33 (m,1H), 7.27 (d, J = 8.0 Hz, 2H).Pharmacology

The compounds provided in the present invention are positive allostericmodulators of mGluR4. As such, these compounds do not appear to bind tothe orthosteric glutamate recognition site, and do not activate themGluR4 by themselves. Instead, the response of mGluR4 to a concentrationof glutamate or mGluR4 agonist is increased when compounds of Formula(I) are present. Compounds of Formula (I) are expected to have theireffect at mGluR4 by virtue of their ability to enhance the function ofthe receptor.

mGluR4 Assay on HEK-Expressing Human mGluR4

The compounds of the present invention are positive allostericmodulators of mGluR4 receptor. Their activity was examined onrecombinant human mGluR4a receptors by detecting changes inintracellular Ca²⁺ concentration, using the fluorescent Ca²⁺-sensitivedye Fluo4-(AM) and a Fluorometric Imaging Plate Reader (FLIPR, MolecularDevices, Sunnyvale, Calif.).

Transfection and Cell Culture

The cDNA encoding the human metabotropic glutamate receptor (hmGluR4),(accession number NM_(—)000841.1, NCBI Nucleotide database browser), wassubcloned into an expression vector containing also the hygromycinresistance gene. In parallel, the cDNA encoding a G protein allowingredirection of the activation signal to intracellular calcium flux wassubcloned into a different expression vector containing also thepuromycin resistance gene. Transfection of both these vectors intoHEK293 cells with PolyFect reagent (Qiagen) according to supplier'sprotocol, and hygromycin and puromycin treatment allowed selection ofantibiotic resistant cells which had integrated stably one or morecopies of the plasmids. Positive cellular clones expressing hmGluR4 wereidentified in a functional assay measuring changes in calcium fluxes inresponse to glutamate or selective known mGluR4 orthosteric agonists andantagonists.

HEK-293 cells expressing hmGluR4 were maintained in media containingDMEM, dialyzed Fetal Calf Serum (10%), Glutamax™ (2 mM), Penicillin (100units/mL), Streptomycin (100 μg/mL), Geneticin (100 μg/mL) andHygromycin-B (40 μg/mL) and puromycin (1 μg/mL) at 37° C./5% CO₂.

Fluorescent Cell Based-Ca²⁺ Mobilization Assay

Human mGluR4 HEK-293 cells were plated out 24 hours prior to FLIPR³⁸⁴assay in black-walled, clear-bottomed, poly-L-ornithine-coated 384-wellplates at a density of 25,000 cells/well in a glutamine/glutamate freeDMEM medium containing foetal bovine serum (10%), penicillin (100units/mL) and streptomycin (100 μg/mL) at 37° C./5% CO₂.

On the day of the assay, the medium was aspirated and the cells wereloaded with a 3 μM solution of Fluo-4-AM (LuBioScience, Lucerne,Switzerland) in 0.03% pluronic acid. After 1 hour at 37° C./5% CO₂, thenon incorporated dye was removed by washing cell plate with the assaybuffer and the cells were left in the dark at room temperature for sixhours before testing. All assays were performed in a pH 7.4buffered-solution containing 20 mM HEPES, 143 mM NaCl, 6 mM KCl, 1 mMMgSO₄, 1 mM CaCl₂, 0.125 mM sulfapyrazone and 0.1% glucose.

After 10 s of basal fluorescence recording, various concentrations ofthe compounds of the invention were added to the cells. Changes influorescence levels were first monitored for 180 s in order to detectany agonist activity of the compounds. Then the cells were stimulated byan EC₂₅ glutamate concentration for an additional 110 s in order tomeasure enhancing activities of the compounds of the invention. EC₂₅glutamate concentration is the concentration giving 25% of the maximalglutamate response.

The concentration-response curves of representative compounds of thepresent invention were generated using the Prism GraphPad software(Graph Pad Inc, San Diego, USA). The curves were fitted to afour-parameter logistic equation:(Y=Bottom+(Top-Bottom)/(1+10^((Log EC ₅₀ −X)*Hill Slope)allowing the determination of EC₅₀ values.

The Table 4 below represents the mean EC₅₀ obtained from at least threeindependent experiments of selected molecules performed in duplicate.

TABLE 4 Activity data for selected compounds Compound no. Ca²⁺ Flux*1-1 + 1-2 +++ 1-5 ++ 1-7 +++ 1-10 +++ 1-18 ++ 1-21 +++ *Table legend:(+): 1 μM < EC₅₀ < 10 μM (++): 100 nM < EC₅₀ < 1 μM (+++): EC₅₀ < 100 nM

The results shown in Table 4 demonstrate that the compounds described inthe present invention are positive allosteric modulators of human mGluR4receptors. These compounds do not have activity by themselves but theyrather increase the functional activity and/or maximal efficacy ofglutamate or mGluR4 agonist.

Thus, the positive allosteric modulators provided in the presentinvention are expected to increase the effectiveness of glutamate ormGluR4 agonists at mGluR4 receptor. Therefore, these positive allostericmodulators are expected to be useful for treatment of variousneurological and psychiatric disorders associated with glutamatedysfunction described to be treated herein and others that can betreated by such positive allosteric modulators.

The compounds of the invention can be administered either alone, or incombination with other pharmaceutical agents effective in the treatmentof conditions mentioned above.

Formulation Examples

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

In this Example, active ingredient can be replaced by the same amount ofany of the compounds according to the present invention, in particularby the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 mL.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol andwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

The invention claimed is:
 1. A compound according to Formula (II):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof or an N-oxide form thereof,wherein: X² is selected from the group of C and N representing a 5membered heteroaryl ring which may further be substituted by radical(A)_(m) where: m is an integer ranging from 0 to 1; (A)_(m) radical isselected from the group of hydrogen, halogen, —CN, —OH, —CF₃, —SH, —NH₂and an optionally substituted radical selected from the group of—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl, —(C₂-C₆)alkenyl,—(C₃-C₇)cycloalkyl, —(C₃-C₈)cycloalkenyl, —(C₁-C₆)cyanoalkyl, aryl,—(C₁-C₆)alkylene-aryl, heteroaryl, —(C₁-C₆)alkylene-heteroaryl,heterocycle, —(C₀-C₆)alkylene-OR¹, —O—(C₂-C₆)alkylene-OR¹,—NR¹(C₂-C₆)alkylene-OR², —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR¹—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—NR¹—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)haloalkylene-OR¹,—(C₁-C₆)haloalkylene-NR¹R², —(C₀-C₆)alkylene-S—R¹,—O—(C₂-C₆)alkylene-S—R¹, —NR¹-(C₂-C₆)alkylene-S—R²,—(C₀-C₆)alkylene-S(═O)—R¹, —O—(C₁-C₆)alkylene-S(═O)—R¹,—NR¹—(C₁-C₆)alkylene-S(═O)—R², —(C₀-C₆)alkylene-S(═O)₂—R¹,—O—(C₁-C₆)alkylene-S(═O)₂—R¹, —NR¹—(C₁-C₆)alkylene-S(═O)₂—R²,—(C₀-C₆)alkylene-NR¹R², —O—(C₂-C₆)alkylene-NR¹R²,—NR¹—(C₂-C₆)alkylene-NR²R³, —(C₀-C₆)alkylene-S(═O)₂NR¹R²,—O—(C₁-C₆)alkylene-S(═O)₂NR¹R², —NR¹—(C₁-C₆)alkylene-S(═O)₂NR²R³,—(C₀-C₆)alkylene-NR¹—S(═O)₂R², —O—(C₂-C₆)alkylene-NR¹—S(═O)₂R²,—NR¹—(C₂-C₆)alkylene-NR²—S(═O)₂R³, —(C₀-C₆)alkylene-C(═O)—NR¹R²,—O—(C₁-C₆)alkylene- C(═O)-NR¹R²,—NR¹—(C₁-C₆)alkylene-C(═O)-NR²R³,—(C₀-C₆)alkylene-NR¹C(═O)-R²,—O—(C₂-C₆)alkylene-NR¹C(═O))—R², —NR¹—(C₂-C₆)alkylene-NR²C(═O)—R³,—(C₀-C₆)alkylene-C(═O)—R¹, —O—(C₁-C₆)alkylene-C(═O)—R¹ and—NR¹—(C₁-C₆)alkylene-C(═O)—R²; R¹, R² and R³ are each independentlyhydrogen or an optionally substituted radical selected from the group of—(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl,—(C₃-C₇)cycloalkyl, —(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl,—(C₁-C₆)alkylene-heteroaryl, aryl, heterocycle and—(C₁-C₆)alkylene-aryl; Any two radicals of R(R¹, R² or R³) may be takentogether to form an optionally substituted 3 to 10 membered carbocyclicor heterocyclic ring; M is selected from an optionally substituted 3 to10 membered ring selected from the group of aryl, heteroaryl,heterocyclic and cycloalkyl; B radical is selected from the group ofhydrogen, halogen, —CN, —OH, —CF₃, —SH, —NH₂ and an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl, —(C₂-C₆)alkenyl, —(C₃-C₇)cycloalkyl,—(C₃-C₈)cycloalkenyl, —(C₁-C₆)cyanoalkyl, —(C₁-C₆)alkylene-heteroaryl,—(C₁-C₆)alkylene-aryl, aryl, heteroaryl, heterocycle,—(C₀-C₆)alkylene-OR⁴, —O—(C₂-C₆)alkylene-OR⁴, —NR⁴(C₂-C₆)alkylene-OR⁵,—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —O-(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—NR⁴—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—NR⁴—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)haloalkylene-OR⁴,—(C₁-C₆)haloalkylene-NR⁴R⁵, —(C₀-C₆)alkylene-S—R⁴,—O—(C₂-C₆)alkylene-S—R⁴, —NR⁴—(C₂-C₆)alkylene-S—R⁵,—(C₀-C₆)alkylene-S(═O)—R⁴, —O—(C₁-C₆)alkylene-S(═O)—R⁴,—NR⁴-(C₁-C₆)alkylene-S(═O)—R⁵, —(C₀-C₆)alkylene-S(═O)₂—R⁴,—O—(C₁-C₆)alkylene-S(═O)₂—R⁴, —NR⁴—(C₁-C₆)alkylene-S(═O)₂—R⁵,—(C₀-C₆)alkylene-NR⁴R⁵, —O—(C₂-C₆)alkylene-NR⁴R⁵,—NR⁴—(C₂-C₆)alkylene-NR⁵R⁶, —(C₀-C₆)alkylene-S(═O)₂NR⁴R⁵,—O—(C₁-C₆)alkylene-S(═O)₂NR⁴R⁵, —NR⁴—(C₁-C₆)alkylene-S(═O)₂NR⁵R⁶,—(C₀-C₆)alkylene-NR⁴—S(═O)₂R⁵, —O—(C₂-C₆)alkylene-NR⁴—S(═O)₂R⁵,—NR⁴—(C₂-C₆)alkylene-NR⁵—S(═O)₂R⁶, —(C₀-C₆)alkylene-C(═O)—NR⁴R⁵,—O—(C₁-C₆)alkylene-C(═O)—NR⁴R⁵, —NR⁴—(C₁-C₆)alkylene-C(═O)—NR⁵R⁶,—(C₀-C₆)alkylene-NR⁴C(═O)—R⁵, —O—(C₂-C₆)alkylene-NR⁴C(═O)—R⁵,—NR⁴—(C₂-C₆)alkylene-NR⁵C(═O)—R⁶, —(C₀-C₆)alkylene-C(═O)—R⁴,—O—(C₁-C₆)alkylene-C(═O)—R⁴ and —NR⁴—(C₁-C₆)alkylene-C(═O)—R⁵; R⁴, R⁵and R⁶ are each independently hydrogen or an optionally substitutedradical selected from the group of —(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl,—(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl, —(C₄-C₁₀)alkylene-cycloalkyl,heteroaryl, —(C₁-C₆)alkylene-heteroaryl, aryl, heterocycle and—(C₁-C₆)alkylene-aryl; Any two radicals of R(R⁴, R⁵ or R⁶) may be takentogether to form an optionally substituted 3 to 10 membered carbocyclicor heterocyclic ring; and with the proviso (i) that: M can not be anazaadamantanyl.
 2. A compound according to claim 1 having the Formula(III):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof or an N-oxide form thereof,wherein: M is selected from an optionally substituted 3 to 10 memberedring selected from the group of aryl, heteroaryl and cycloalkyl.
 3. Acompound according to claim 2 having the Formula (III) wherein: Aradical is selected from the group of hydrogen, halogen, —CN, —CF₃, andan optionally substituted radical selected from the group of—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl, aryl, heteroaryl,heterocycle, —(C₀-C₆)alkylene-OR¹, —NR¹(C₂-C₆)alkylene-OR²,—(C₀-C₆)alkylene-NR¹R², —NR¹—(C₂-C₆)alkylene-NR²R³,—(C₀-C₆)alkylene-C(═O)—NR¹R² and —(C₀-C₆)alkylene-C(═O)—R¹; R¹ and R²are each independently hydrogen or an optionally substituted radicalselected from the group of —(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl,—(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl, —(C₄-C₁)alkylene-cycloalkyl,heteroaryl, —(C₁-C₆)alkylene-heteroaryl, aryl,—(C₁-C₆)alkylene-heterocycle, heterocycle and —(C₁-C₆)alkylene-aryl; Anytwo radicals of R(R¹ or R²) may be taken together to form an optionallysubstituted 3 to 10 membered carbocyclic or heterocyclic ring; B radicalis selected from the group of hydrogen, halogen, —CN, —CF₃ and anoptionally substituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl, aryl, heteroaryl, heterocycle,—(C₀-C₆)alkylene-OR⁴, —NR¹(C₂-C₆)alkylene-OR², —(C₀-C₆)alkylene-NR⁴R⁵,—O—(C₂-C₆)alkylene-NR⁴R⁵, —NR⁴—(C₂-C₆)alkylene-NR⁵R⁶,—(C₀-C₆)alkylene-C(═O)—NR⁴R⁵ and —(C₀-C₆)alkylene-C(═O)—R⁴; R⁴ and R⁵are each independently hydrogen or an optionally substituted radicalselected from the group of —(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl,—(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl, —(C₄-C₁₀)alkylene-cycloalkyl,heteroaryl, —(C₁-C₆)alkylene-heteroaryl, aryl, heterocycle and—(C₁-C₆)alkylene-aryl; and Any two radicals of R(R⁴ or R⁵) may be takentogether to form an optionally substituted 3 to 10 membered carbocyclicor heterocyclic ring.
 4. A compound according to claim 3 having theFormula (III) wherein: A radical is selected from the group of hydrogen,halogen and —CN; B radical is selected from the group of hydrogen,halogen, —CF₃ and an optionally substituted radical selected from thegroup of —(C₁-C₆)alkyl, and —(C₀-C₆)alkylene-C(═O)—R⁴; and R⁴ is—(C₁-C₆)alkyl.
 5. A compound according to claim 1 having the Formula(IV):


6. A compound according to claim 5 having the Formula (IV) wherein: Bradical is selected from the group of hydrogen, —CF₃ and an optionallysubstituted radical —(C₁-C₆)alkyl; and M is selected from an optionallysubstituted 3 to 10 membered ring selected from the group of aryl andheteroaryl.
 7. A compound as in any one of claims 1 to 6, which canexist as optical isomers, wherein said compound is either the racemicmixture or one or both of the individual optical isomers.
 8. A compoundselected from: 3-(3-Methyl-1H-pyrazol-4-yl)-5-phenoxy-1,2,4-thiadiazole;5-(Pyridin-2-yloxy)-3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazole;5-(6-Chloropyridin-2-yloxy)-3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazole;4-(5-Methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yloxy)thiazole;2-(2,6-Difluorophenoxy)-4-(1H-pyrazol-4-yl)thiazole;4-(1H-Pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole;2-(6-Chloropyridin-2-yloxy)-4-(3-methyl-1H-pyrazol-4-yl)thiazole;2-(3-Fluoropyridin-2-yloxy)-4-(3-methyl-1H-pyrazol-4-yl)thiazole;1-(4-(2-(6-Methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazol-3-yl)ethanone;2-(6-Methylpyridin-2-yloxy)-4-(1H-pyrazol-4-yl)thiazole;4-(3-Methyl-1H-pyrazol-4-yl)-2-(6-methylpyridin-2-yloxy)thiazole;2-(6-Chloropyridin-2-yloxy)-4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole;2-(Pyridin-2-yloxy)-4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole;2-(Cyclohexyloxy)-4-(1H-pyrazol-4-yl)thiazole;2-(2,4-Difluorophenoxy)-4-(1H-pyrazol-4-yl)thiazole;2-(6-Methylpyrazin-2-yloxy)-4-(1H-pyrazol-4-yl)thiazole;1-(4-(2-(2,4-Difluorophenoxy)thiazol-4-yl)-1H-pyrazol-3-yl)ethanone;2-(5-Fluoropyridin-2-yloxy)-4-(1H-pyrazol-4-yl)thiazole;5-Chloro-4-(1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole;4-(1H-Pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile; and2-(6-Chloropyridin-2-yloxy)-4-(1H-pyrazol-4-yl)thiazole-5-carbonitrileor pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof or an N-oxide form thereof.
 9. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claim 2 and a pharmaceutically acceptablecarrier and/or excipient.
 10. A compound according to claim 1, for usein the treatment of a condition which is affected or facilitated by theneuromodulatory effect of mGluR4 allosteric modulators.
 11. A compoundaccording to claim 1, for use in the treatment of metabolic disordersassociated with glutamate dysfunction.
 12. A compound according to claim1, for use in the treatment of generalized anxiety disorders.
 13. Acomposition according to claim 9, for use in the treatment of acondition which is affected or facilitated by the neuromodulatory effectof mGluR4 allosteric modulators.
 14. A composition according to claim 9,for use in the treatment of metabolic disorders associated withglutamate dysfunction.
 15. A composition according to claim 9, for usein the treatment of generalized anxiety disorders.